Heterocycle derivatives as histone deacetylase (HDAC) inhibitors

ABSTRACT

The present invention relates to compounds of formula I: 
                         
or pharmaceutically acceptable salts or tautomers thereof, which are inhibitors of histone deacetylase (HDAC). The compounds of the present invention are useful for treating cellular proliferative diseases, including cancer. Further, the compounds of the present invention are useful for treating neurodegenerative diseases, schizophrenia and stroke among other diseases.

PRIORITY CLAIM

This application is a §371 National Stage Application ofPCT/GB2005/004743, filed on Dec. 9, 2005, which claims priority from GBProvisional Application Serial Numbers 0516435.5, filed on Aug. 11,2005, and 0427138.3, filed on Dec. 10, 2004.

The present invention relates to heterocycle derivatives that areinhibitors of histone deacetylase (HDAC). The compounds of the presentinvention are useful for treating cellular proliferative diseases,including cancer. Further, the compounds of the present invention areuseful for treating neurodegenerative diseases, schizophrenia and strokeamong other diseases.

DNA in the nucleus of the cell exists as a hierarchy of compactedchromatin structures. The basic repeating unit in chromatin is thenucleosome. The nucleosome consists of a histone octamer of proteins inthe nucleus of the cell around which DNA is wrapped twice. The orderlypackaging of DNA in the nucleus plays an important role in thefunctional aspects of gene regulation. Covalent modifications of thehistones have a key role in altering chromatin higher order structureand function and ultimately gene expression. The covalent modificationof histones, such as acetylation, occurs by enzymatically mediatedprocesses.

Regulation of gene expression through the inhibition of the nuclearenzyme histone deacetylase (HDAC) is one of several possible regulatorymechanisms whereby chromatin activity can be affected. The dynamichomeostasis of the nuclear acetylation of histones can be regulated bythe opposing activity of the enzymes histone acetyl transferase (HAT)and histone deacetylase (HDAC). Transcriptionally silent chromatin canbe characterized by nucleosomes with low levels of acetylated histones.Acetylation reduces the positive charge of histones, thereby expandingthe structure of the nucleosome and facilitating the interaction oftranscription factors with the DNA. Removal of the acetyl group restoresthe positive charge, condensing the structure of the nucleosome. Histoneacetylation can activate DNA transcription, enhancing gene expression.Histone deacetylase can reverse the process and can serve to repressgene expression. See, for example, Grunstein, Nature 389, 349-352(1997); Pazin et al., Cell 89, 325-328 (1997); Wade et al., TrendsBiochem. Sci. 22, 128-132 (1997); and Wolffe, Science 272, 371-372(1996).

WO 04/072047, published on 26 Aug. 2004, discloses indoles,benzimidazoles and naphthimidazoles as HDAC inhibitors, which compoundsdiffer in structure to the compounds of the present invention.

WO 99/64401 and WO 02/10140 disclose structurally related imidazolylderivatives as somatostatin receptor agonists and antagonists.

SUMMARY OF THE INVENTION

The present invention relates to heterocycle derivatives that areinhibitors of histone deacetylase (HDAC). The compounds of the presentinvention are useful for treating cellular proliferative diseases,including cancer. Further, the compounds of the present invention areuseful for treating neurodegenerative diseases, schizophrenia and strokeamong other diseases.

The present invention provides compounds of formula (I):

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are useful in the inhibition of histonedeacetylase. The present invention provides compounds of formula (I):

p is 0, 1, 2, 3, 4 or 5;

q is 1, 2, 3 or 4;

t is 0 or 1;

D is absent, (CH₂)_(b) or (CH═CH)_(c);

b is 1, 2 or 3;

c is 1, 2 or 3;

X is C or S═O;

Het is a 5 membered unsaturated heterocycle containing 1, 2, 3 or 4heteroatoms independently selected from N, O and S, but not more thanone of which is O or S, or a 6 membered unsaturated heterocyclecontaining 1, 2, 3 or 4 heteroatoms independently selected from N and O;optionally substituted by one or more groups independently chosen fromcyano, halogen, hydroxy, oxo, nitro, amino, C₁₋₆alkylamino,di(C₁₋₆alkyl)amino, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl and C₆₋₁₀aryl;

R¹ is hydrogen, hydroxy, halogen, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl,C₁₋₆alkyl, haloC₁₋₆alkyl, N(R^(h))₂ wherein R^(h) is independentlyselected from hydrogen, C₁₋₆alkyl, C₆₋₁₀aryl and C₆₋₁₀arylC₁₋₆alkyl;C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5 or 6 membered saturated or partiallysaturated heterocycle containing 1, 2 or 3 heteroatoms independentlyselected from N, O and S, 5 membered unsaturated heterocycle containing1, 2, 3 or 4 heteroatoms independently selected from O, N and S, but notmore than one of which is O or S, 6 membered unsaturated heterocyclecontaining 1, 2 or 3 nitrogen atoms, or 8-13 membered unsaturated orpartially saturated heterocycle containing heteroatoms independentlyselected from O, N and S; any of which rings being optionallysubstituted by one or more groups independently chosen from cyano,halogen, nitro, oxo, hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl, carboxy,C₆₋₁₀aryl, C₆₋₁₀aryloxy, C₆₋₁₀arylcarbonyl, N(R^(a))₂ wherein R^(a) isindependently selected from hydrogen, C₁₋₆alkyl, C₆₋₁₀aryl,C₁₋₆alkylcarbonyl and C₆₋₁₀arylcarbonyl; C₁₋₆alkylN(R^(a))₂ and(CO)_(d)R^(k) wherein d is 0 or 1 and R^(k) is as defined below;

R² is hydrogen, hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy,C₃₋₁₀cycloalkyl, hydroxyC₁₋₆alkyl, N(R^(b))₂, —(C═O)—N(R^(c))₂ whereinR^(c) is independently selected from hydrogen and C₁₋₆alkyl;C₁₋₆alkylS(O)_(w)R^(g) wherein R^(g) is as defined below and w is zero,one or two; a 5 membered unsaturated heterocycle containing 1, 2, 3 or 4heteroatoms independently selected from N, O and S, but not more thanone of which is O or S, or a 6 membered unsaturated heterocyclecontaining 1, 2, or 3 heteroatoms independently selected from N and O;any of which rings being optionally substituted by one or more groupsindependently chosen from cyano, halogen, hydroxy, oxo, nitro, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, C₁₋₆alkyl, haloC₁₋₆alkyl,C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyland C₆₋₁₀aryl;

R³ is hydrogen, halogen, hydroxy, cyano, C₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₃₋₁₀cycloalkyl,haloC₃₋₁₀cycloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, nitro, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, C₆₋₁₀aryl, C₆₋₁₀arylC₁₋₆alkyl,C₆₋₁₀arylC₁₋₆alkoxy; 6-13 membered partially saturated hydrocarbon ring;4, 5 or 6 membered saturated or partially saturated heterocyclecontaining 1, 2 or 3 heteroatoms independently selected from N, O and S,optionally bridged by a C₁₋₄alkyl group; 5 membered unsaturatedheterocycle containing 1, 2, 3 or 4 heteroatoms independently selectedfrom N, O and S, but not more than one of which is O or S; 6 memberedunsaturated heterocycle containing 1, 2 or 3 nitrogen atoms; or a 7-15membered saturated, partially saturated or unsaturated heterocyclecontaining heteroatoms independently selected from N, O or S; any ofwhich rings being optionally substituted by one or more groupsindependently chosen from (CH₂)_(m)(CO)_(n)R^(d);

m is 0, 1, 2 or 3;

n is 0, 1 or 2;

R⁴ and R⁵ are independently selected from hydrogen and C₁₋₆alkyl;

R⁶ and R⁸ are independently hydrogen, C₁₋₆alkyl, a 5 or 6 memberedsaturated or partially saturated heterocycle containing 1, 2 or 3heteroatoms independently selected from N, O and S or a 6 memberedunsaturated heterocycle containing 1, 2 or 3 nitrogen atoms; each ofwhich rings being optionally substituted by one or more groupsindependently chosen from halogen, nitro, amino, cyano, oxo, hydroxy,C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₃₋₁₀cycloalkyl,C₂₋₆alkenyl and C₂₋₆alkynyl; or

R⁶ and R⁸ together represent an oxo group;

each R^(b) is independently hydrogen, C₁₋₆alkyl, hydroxy, C₁₋₆alkoxy,C₁₋₆alkylS(O)_(w)R^(g) wherein R^(g) is as defined below and w is zero,one or two; SO₂R^(g) wherein R^(g) is C₁₋₆alkyl, haloC₁₋₆alkyl, amino,C₁₋₆alkylamino or di(C₁₋₆alkyl)amino; or a ring which is C₆₋₁₀aryl,C₆₋₁₀arylC₁₋₆alkyl or a 5 membered unsaturated heterocycle containing 1,2, 3 or 4 heteroatoms independently selected from N, O and S, but notmore than one of which is O or S, the ring being optionally substitutedby one or more groups independently selected from amino, hydroxy, nitro,cyano, halogen, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy and haloC₁₋₆alkoxy;

each R^(d) is halogen, hydroxy, cyano, C₁₋₆alkyl, haloC₁₋₆alkyl,haloC₁₋₆alkylcarbonyl, haloC₁₋₆alkylcarbonyloxy, C₁₋₆alkoxy,haloC₁₋₆alkoxy, carboxy, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl, nitro,oxo, SO₂N(R^(e))₂, N(R^(e))₂ wherein R^(e) is independently selectedfrom hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, carboxy andC₁₋₆alkyloxycarbonyl; C₁₋₆alkylN(R^(e))₂, C₆₋₁₀aryl;C₆₋₁₀arylC₁₋₆alkoxy, 5 or 6 membered saturated or partially saturatedheterocycle containing 1, 2 or 3 heteroatoms independently selected fromN, O or S, optionally bridged by a C₁₋₄alkyl group; 5 memberedunsaturated heterocycle containing 1, 2, 3 or 4 heteroatomsindependently selected from N, O and S, but not more than one of whichis O or S; a 5 or 6 membered spiro ring containing zero, one or twoheteroatoms independently selected from N, O or S, or a 6 memberedunsaturated heterocycle containing 1, 2 or 3 nitrogen atoms; any ofwhich rings may be optionally substituted by one or more groupsindependently chosen from halogen, hydroxy, amino, cyano, C₁₋₆alkyl,haloC₁₋₆alkyl, C₁₋₆alkoxy and haloC₁₋₆alkoxy;

R^(k) is NSO₂R^(g), 5 or 6 membered saturated or partially saturatedheterocycle containing 1, 2 or 3 heteroatoms independently selected fromN, O and S or a 5 membered unsaturated heterocycle containing 1, 2, 3 or4 heteroatoms independently selected from N, O and S, but not more thanone of which is O or S; any of which rings being optionally substitutedby one or more groups independently selected from halogen and C₁₋₆alkyl:

or a pharmaceutically acceptable salt or tautomer thereof.

In an embodiment:

D is absent;

p is 0, 1, 2 or 3;

q is 1, 2, 3 or 4;

t is 0 or 1;

X is C or S═O;

Het is a 5 membered unsaturated heterocycle containing 1, 2, 3 or 4heteroatoms independently selected from N, O and S, but not more thanone of which is O or S, or a 6 membered unsaturated heterocyclecontaining 1, 2, 3 or 4 heteroatoms independently selected from N and O;optionally substituted by one or more groups independently chosen fromcyano, halogen, hydroxy, oxo, nitro, amino, C₁₋₆alkylamino,di(C₁₋₆alkyl)amino, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl and C₆₋₁₀aryl;

R¹ is hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl, C₆₋₁₀aryl, 5 memberedunsaturated heterocycle containing 1, 2, 3 or 4 heteroatomsindependently selected from O, N and S, but not more than one of whichis O or S, 6 membered unsaturated heterocycle containing 1, 2 or 3nitrogen atoms, or 8-10 membered unsaturated or partially saturatedheterocycle containing heteroatoms independently selected from O, N andS; any of which rings being optionally substituted by one or more groupsindependently chosen from cyano, halogen, nitro, oxo, hydroxy,C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₁₋₆alkylcarbonyl,C₁₋₁₀aryl, C₆₋₁₀aryloxy, C₆₋₁₀arylcarbonyl and N(R^(a))₂ wherein R^(a)is independently selected from hydrogen, C₁₋₆alkyl, C₆₋₁₀aryl,C₁₋₆alkylcarbonyl and C₆₋₁₀arylcarbonyl;

R² is hydrogen, hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,N(R^(b))₂, —(C═O)—N(R^(c))₂ wherein R^(c) is independently selected fromhydrogen and C₁₋₆alkyl; a 5 membered unsaturated heterocycle containing1, 2, 3 or 4 heteroatoms independently selected from N, O and S, but notmore than one of which is O or S, or a 6 membered unsaturatedheterocycle containing 1, 2, or 3 heteroatoms independently selectedfrom N and O; any of which rings being optionally substituted by one ormore groups independently chosen from cyano, halogen, hydroxy, oxo,nitro, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, C₁₋₆alkyl,haloC₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₃₋₁₀cycloalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl and C₆₋₁₀aryl;

R³ is hydrogen, halogen, hydroxy, cyano, C₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₃₋₁₀cycloalkyl,haloC₃₋₁₀cycloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, nitro, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, C₆₋₁₀aryl, C₆₋₁₀arylC₁₋₆alkyl,C₆₋₁₀arylC₁₋₆alkoxy; 4, 5 or 6 membered saturated or partially saturatedheterocycle containing 1, 2 or 3 heteroatoms independently selected fromN, O and S, optionally bridged by a C₁₋₄alkyl group; 5 memberedunsaturated heterocycle containing 1, 2, 3 or 4 heteroatomsindependently selected from N, O and S, but not more than one of whichis O or S; 6 membered unsaturated heterocycle containing 1, 2 or 3nitrogen atoms; or a 7-13 membered saturated, partially saturated orunsaturated heterocycle containing heteroatoms independently selectedfrom N, O or S; any of which rings being optionally substituted by oneor more groups independently chosen from R^(d);

R⁴ and R⁵ are independently selected from hydrogen and C₁₋₆alkyl;

R⁶ and R⁸ are independently hydrogen, C₁₋₆alkyl, a 5 or 6 memberedsaturated or partially saturated heterocycle containing 1, 2 or 3heteroatoms independently selected from N, O and S or a 6 memberedunsaturated heterocycle containing 1, 2 or 3 nitrogen atoms; each ofwhich rings being optionally substituted by one or more groupsindependently chosen from halogen, nitro, amino, cyano, oxo, hydroxy,C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₃₋₁₀cycloalkyl,C₂₋₆alkenyl and C₂₋₆alkynyl; or

R⁶ and R⁸ together represent an oxo group;

each R^(b) is independently hydrogen, C₁₋₆alkyl, hydroxy, C₁₋₆alkoxy,SO₂R^(g) wherein R^(g) is C₁₋₆alkyl or haloC₁₋₆alkyl; or a ring which isC₆₋₁₀aryl, C₆₋₁₀arylC₁₋₆alkyl or a 5 membered unsaturated heterocyclecontaining 1, 2, 3 or 4 heteroatoms independently selected from N, O andS, but not more than one of which is O or S, the ring being optionallysubstituted by one or more groups independently selected from amino,hydroxy, nitro, cyano, halogen, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy andhaloC₁₋₆alkoxy;

R^(d) is halogen, hydroxy, cyano, C₁₋₆alkyl, haloC₁₋₆alkyl,haloC₁₋₆alkylcarbonyl, haloC₁₋₆alkylcarbonyloxy, C₁₋₆alkoxy,haloC₁₋₆alkoxy, carboxy, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl, nitro,oxo, SO₂N(R^(e))₂, N(R^(e))₂ wherein R^(e) is independently selectedfrom hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, carboxy andC₁₋₆alkyloxycarbonyl; or C₁₋₁₀aryl; 5 or 6 membered saturated orpartially saturated heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O or S, optionally bridged by a C₁₋₄alkylgroup; 5 membered unsaturated heterocycle containing 1, 2, 3 or 4heteroatoms independently selected from N, O and S, but not more thanone of which is O or S; or a 6 membered unsaturated heterocyclecontaining 1, 2 or 3 nitrogen atoms; any of which rings may beoptionally substituted by one or more groups independently chosen fromhalogen, hydroxy, amino, cyano, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy andhaloC₁₋₆alkoxy;

or a pharmaceutically acceptable salt thereof.

In an embodiment of the previous embodiment:

R¹ is hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl, C₆₋₁₀aryl, 5 memberedunsaturated heterocycle containing 1, 2, 3 or 4 heteroatomsindependently selected from O, N and S, but not more than one of whichis O or S, 6 membered unsaturated heterocycle containing 1, 2 or 3nitrogen atoms, or 8-10 membered unsaturated heterocycle containingheteroatoms independently selected from O, N and S; any of which ringsbeing optionally substituted by one or more groups independently chosenfrom cyano, halogen, nitro, oxo, hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl,C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₁₋₆alkylcarbonyl, C₆₋₁₀aryl, C₆₋₁₀aryloxy,C₆₋₁₀arylcarbonyl and N(R^(a))₂ wherein R^(a) is independently selectedfrom hydrogen, C₁₋₆alkyl, C₆₋₁₀aryl, C₁₋₆alkylcarbonyl andC₆₋₁₀arylcarbonyl;

R² is hydrogen, hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl orN(R^(b))₂ wherein R^(b) is independently selected from hydrogen,C₁₋₆alkyl, hydroxy and phenyl optionally substituted by amino, hydroxy,nitro, cyano, halogen or C₁₋₆alkyl; —(C═O)—N(R^(c))₂ wherein R^(c) isindependently selected from hydrogen and C₁₋₆alkyl; a 5 memberedunsaturated heterocycle containing 1, 2, 3 or 4 heteroatomsindependently selected from N, O and S, but not more than one of whichis O or S, or a 6 membered unsaturated heterocycle containing 1, 2, or 3heteroatoms independently selected from N and O; any of which ringsbeing optionally substituted by one or more groups independently chosenfrom cyano, halogen, hydroxy, oxo, nitro, amino, C₁₋₆alkylamino,di(C₁₋₆alkyl)amino, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl and C₆₋₁₀aryl;

R³ is hydrogen, halogen, hydroxy, cyano, C₁₋₆alkyl, haloC₁₋₆alkyl;hydroxyC₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₃₋₁₀cycloalkyl,haloC₃₋₁₀cycloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, nitro, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino; C₆₋₁₀aryl; 4, 5 or 6 memberedsaturated or partially saturated heterocycle containing 1, 2 or 3heteroatoms independently selected from N, O and S, optionally bridgedby a C₁₋₄alkyl group; 5 membered unsaturated heterocycle containing 1,2, 3 or 4 heteroatoms independently selected from N, O and S, but notmore than one of which is O or S; 6 membered unsaturated heterocyclecontaining 1, 2 or 3 nitrogen atoms; or a 7-10 membered saturated,partially saturated or unsaturated heterocycle containing heteroatomsindependently selected from N, O or S; any of which rings beingoptionally substituted by one or more groups independently chosen fromR^(d);

R⁴ and R⁵ are independently selected from hydrogen and C₁₋₆alkyl;

R⁶ is hydrogen, C₁₋₆alkyl, a 5 or 6 membered saturated or partiallysaturated heterocycle containing 1, 2 or 3 heteroatoms independentlyselected from N, O and S or a 6 membered unsaturated heterocyclecontaining 1, 2 or 3 nitrogen atoms; each of which rings beingoptionally substituted by one or more groups independently chosen fromhalogen, nitro, amino, cyano, oxo, hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl,C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₃₋₁₀cycloalkyl, C₂₋₆alkenyl andC₂₋₆alkynyl;

R⁸ is hydrogen;

R^(d) is halogen, hydroxy, cyano, C₁₋₆alkyl, haloC₁₋₆alkyl,haloC₁₋₆alkylcarbonyl, haloC₁₋₆alkylcarbonyloxy, C₁₋₆alkoxy,haloC₁₋₆alkoxy, carboxy, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl, nitro,SO₂N(R^(e))₂, N(R^(e))₂ wherein R^(e) is independently selected fromhydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, carboxy andC₁₋₆alkyloxycarbonyl; or C₁₋₁₀aryl; 5 or 6 membered saturated orpartially saturated heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O or S, optionally bridged by a C₁₋₄alkylgroup; 5 membered unsaturated heterocycle containing 1, 2, 3 or 4heteroatoms independently selected from N, O and S, but not more thanone of which is O or S; or a 6 membered unsaturated heterocyclecontaining 1, 2 or 3 nitrogen atoms; any of which rings may beoptionally substituted by one or more groups independently chosen fromhalogen, hydroxy, amino, cyano, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy andhaloC₁₋₆alkoxy; and

p, q, t, X and Het are as defined above;

or a pharmaceutically acceptable salt thereof.

b is preferably 1 or 2.

c is preferably 1.

Preferably, D is absent, CH₂, CH₂CH₂ or CH═CH.

In an embodiment D is absent.

p is preferably 0, 1, 2, 3 or 4.

p is preferably 0, 1 or 2. In one embodiment p is 0.

q is preferably 2, 3 or 4, especially 3 or 4, and most especially 3.

In one embodiment t is 0.

In another embodiment t is 1 and R⁵ is hydrogen or methyl, preferablymethyl.

In an embodiment of the present invention X is C.

In another embodiment X is S═O.

Preferably, Het is an optionally substituted 5 membered unsaturatedheterocycle containing 1, 2 or 3 heteroatoms independently selected fromN, O and S, but not more than one of which is O or S, or an optionallysubstituted 6 membered unsaturated heterocycle containing 1, 2 or 3nitrogen atoms.

In one embodiment Het is an optionally substituted 5 memberedunsaturated heterocycle containing 1, 2, 3 or 4 heteroatomsindependently selected from N, O and S, but not more than one of whichis O or S.

More particularly Het is an optionally substituted imidazolyl, oxazolyl,triazolyl or thienyl. Further particular Het groups include anoptionally substituted furyl, oxadiazolyl, thiazolyl, pyrazolyl andpyridinyl.

Preferably Het is unsubstituted or substituted by one, two or threegroups. More particularly Het is unsubstituted or monosubstituted.Favoured optional substituents include C₁₋₄alkyl and C₆₋₁₀aryl,especially methyl and phenyl.

In one embodiment Het is unsubstituted.

For the avoidance of doubt R¹ may be attached to any substitutableposition of Het as may any optional substituent on Het.

Thus, particular preferred Het groups include imidazolyl,methylimidazolyl, phenylimidazolyl, phenyloxazolyl, triazolyl andthienyl. Further preferred Het groups include furyl, oxadiazolyl,thiazolyl, oxazolyl, pyrazolyl and pyridinyl.

Specific Het groups are imidazol-2-yl, 4-methylimidazol-2-yl,4-phenylimidazol-2-yl, 4-phenyloxazol-2-yl, 1,2,4-triazol-3-yl,1-methylimidazol-2-yl and 2-thienyl. Further specific Het groups are2-furyl, 1,3,4-oxadiazol-2-yl, 1,3-thiazol-2-yl, 1,2,4-oxadiazol-5-yl,1,3-thiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,3-oxazol-2-yl, imidazol-4-yl,pyrazol-5-yl and pyridin-2-yl.

Preferably R¹ is hydrogen, hydroxy, halogen, C₁₋₆alkylcarbonyl,C₁₋₆alkoxycarbonyl, di(C₁₋₆alkyl)amino,(C₆₋₁₀arylC₁₋₆alkyl)(C₁₋₆alkyl)amino or an optionally substituted ringselected from C₃₋₇cycloalkyl, C₆₋₁₀aryl, 5 or 6 membered saturated orpartially saturated heterocycle, a 5 membered unsaturated heterocyclecontaining 1, 2 or 3 heteroatoms independently selected from N, O and S,but not more than one of which is O or S, a 6 membered unsaturatedheterocycle contains 1, 2 or 3 nitrogen atoms, or a 8, 9, 10, 11, 12 or13 membered unsaturated or partially saturated heterocycle containing 1,2, 3 or 4 heteroatoms independently selected from O, N and S.

Preferably, R¹ is an optionally substituted ring selected fromC₆₋₁₀aryl, a 5 membered unsaturated heterocycle containing 1, 2 or 3heteroatoms independently selected from N, O and S, but not more thanone of which is O or S, a 6 membered unsaturated heterocycle containing1, 2 or 3 nitrogen atoms, or a 8, 9 or 10 membered unsaturated orpartially saturated heterocycle containing 1, 2, 3 or 4 heteroatomsindependently selected from O, N and S.

More particularly, R¹ is an optionally substituted phenyl, naphthyl,thienyl, isoxazolyl, pyridinyl, benzothienyl or thiazolotriazolyl.Further particular R¹ groups include an optionally substituteddihydrobenzodioxinyl, benzothiazolyl, quinolinyl or isoquinolinyl.Further particular R¹ groups include hydroxy, (benzyl)(methyl)amino,dimethylamino, methoxycarbonyl, hydrogen, acetyl, cyclohexyl, bromineand an optionally substituted quinoxalinyl, morpholinyl,tetrahydroisoquinolinyl, indolyl, dibenzo[b,d]furanyl, naphthyridinyl ordihydroquinolinyl.

Favourably R¹ is unsubstituted or substituted by one, two or threegroups. More particularly R¹ is unsubstituted, monosubstituted ordisubstituted. In an embodiment R¹ is monosubstituted. Favoured optionalsubstituents include cyano, halogen, C₁₋₄alkyl, haloC₁₋₄alkyl,C₁₋₄alkoxy, haloC₁₋₄alkoxy and C₆₋₁₀aryl. Further favoured optionalsubstituents include pyrazolyl, di(C₁₋₆alkyl)amino, carboxy,piperidinylcarbonyl, morpholinyl, nitro, (C₁₋₆alkylcarbonyl)amino,C₁₋₆alkoxycarbonyl, amino, aminoC₁₋₆alkyl, tetrazolyl,[(C₁₋₆alkylsulfonyl)amino]carbonyl, hydroxy,[di(C₁₋₆alkyl)amino]C₁₋₆alkyl and oxo; any of which rings beingoptionally substituted by one, two or three C₁₋₆alkyl groups. Examplesof typical optional substituents include cyano, bromine, chlorine,fluorine, methyl, trifluoromethyl, methoxy, difluoromethoxy and phenyl.Further examples of typical optional substituents includedimethylpyrazolyl, dimethylamino, carboxy, piperidinylcarbonyl,morpholinyl, nitro, trifluoromethoxy, ethoxy, acetylamino,methoxycarbonyl, pyrazolyl, amino, aminomethyl, tetrazolyl,[(methylsulfonyl)amino]carbonyl, hydroxy, dimethylaminomethyl and oxo.

Thus, particular preferred R¹ groups include phenyl, cyanophenyl,bromophenyl, chlorophenyl, dichlorophenyl, fluorophenyl, difluorophenyl,trifluoromethylphenyl, bis(trifluoromethyl)phenyl, methoxyphenyl,difluoromethoxyphenyl, biphenyl, naphthyl, thienyl, phenylisoxazolyl,pyridinyl, (chloro)(methyl)benzothienyl,(methyl)(trifluoromethyl)thiazolotriazolyl and benzothienyl. Furtherpreferred R¹ groups are dihydrobenzodioxinyl, benzothiazolyl,methoxyquinolinyl, quinolinyl and isoquinolinyl. Further preferred R¹groups are hydroxy, quinoxalinyl, methoxynaphthyl, morpholinyl,benzyl(methyl)amino, tetrahydroisoquinolinyl, methylquinolinyl, indolyl,(dimethylpyrazolyl)phenyl, (dimethylamino)phenyl,(fluoro)(methoxy)phenyl, carboxyphenyl, dibenzo[b,d]furanyl,(piperidinylcarbonyl)phenyl, dimethylamino, methoxycarbonyl,dimethoxynaphthyl, morpholinylphenyl, nitrophenyl,trifluoromethoxyphenyl, ethoxyphenyl, acetylaminophenyl,(methoxycarbonyl)phenyl, hydrogen, bromophenyl, pyrazolylphenyl,aminophenyl, dimethoxyphenyl, (fluoro)(trifluoromethyl)phenyl,(aminomethyl)phenyl, (aminomethyl)(fluoro)phenyl, tetrazolylphenyl,{[(methylsulfonyl)amino]carbonyl}phenyl, acetyl, cyclohexyl, bromine,hydroxyphenyl, (dimethylaminomethyl)phenyl, fluoroquinolinyl,naphthyridinyl and oxodihydroquinolinyl.

Specific R¹ groups are phenyl, 3-cyanophenyl, 4-cyanophenyl,4-bromophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,3,4-dichlorophenyl, 4-fluorophenyl, 3,4-difluorophenyl,3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl,3,5-bis(trifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-(difluoromethoxy)phenyl, biphen-4-yl, 2-naphthyl, 3-thienyl,3-phenylisoxazol-5-yl, 2-pyridinyl, 5-chloro-3-methyl-1-benzothien-2-yl,6-methyl-2-(trifluoromethyl) [1,3]thiazolo[3,2-b][1,2,4]triazol-5-yl and1-benzothien-3-yl. Further specific R¹ groups are 3,5-dichlorophenyl,2,3-dihydro-1,4-benzodioxin-6-yl, 2,3-dihydro-1,4-benzodioxin-5-yl,1,3-benzothiazol-2-yl, 1-benzothien-2-yl, 4-methoxyquinolin-2-yl,quinolin-3-yl, quinolin-6-yl, quinolin-2-yl and isoquinolin-3-yl.Further specific R¹ groups are quinolin-8-yl, hydroxy, quinoxalin-2-yl,3-methoxy-2-naphthyl, morpholin-4-yl, benzyl(methyl)amino,1,2,3,4-tetrahydroisoquinolin-2-yl, 2-methylquinolin-5-yl,quinolin-5-yl, 8-methylquinolin-5-yl, 8-methoxyquinolin-5-yl,1-benzothien-7-yl, 1H-indol-5-yl,3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl, 4-(dimethylamino)phenyl,2-fluoro-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-carboxyphenyl,biphen-2-yl, dibenzo[b,d]furan-4-yl, 3-(piperidin-1-ylcarbonyl)phenyl,quinoxalin-6-yl, dimethylamino, methoxycarbonyl,1,4-dimethoxy-2-naphthyl, 3,5-dimethoxy-2-naphthyl, 2-thienyl,1-naphthyl, 2-(morpholin-4-yl)phenyl, 3-nitrophenyl, pyridin-3-yl,3-(trifluoromethoxy)phenyl, 4-(trifluoromethoxy)phenyl,2-(trifluoromethyl)phenyl, 2-fluorophenyl, 3-ethoxyphenyl,4-ethoxyphenyl, 4-(acetylamino)phenyl, 2-(methoxycarbonyl)phenyl,hydrogen, 3-bromophenyl, pyridin-4-yl, 4-(1H-pyrazol-1-yl)phenyl,2-nitrophenyl, 3-aminophenyl, 2,4-dimethoxyphenyl,2-fluoro-5-trifluoromethylphenyl, 3-(aminomethyl)phenyl,2-(aminomethyl)-4-fluorophenyl, biphen-3-yl, 3-(1H-tetrazol-5-yl)phenyl,3-{[(methylsulfonyl)amino]carbonyl}phenyl, acetyl, cyclohexyl, bromine,4-carboxyphenyl, 3-hydroxyphenyl, 4-[(dimethylamino)methyl]phenyl,2-carboxyphenyl, 2-fluoroquinolin-3-yl, quinoxalin-6-yl,8-methoxyquinolin-5-yl, 2-methoxyquinolin-3-yl, 1,8-naphthyridin-2-yl,1,6-naphthyridin-2-yl, 1,6-naphthyridin-8-yl and2-oxo-1,2-dihydroquinolin-3-yl.

In an embodiment, R¹ is hydroxy, halogen, C₁₋₆alkylcarbonyl, N(R^(h))₂wherein R^(h) is independently selected from hydrogen, C₁₋₆alkyl,C₁₋₁₀aryl and C₆₋₁₀arylC₁₋₆alkyl; C₃₋₁₀cycloalkyl, 5 or 6 memberedsaturated or partially saturated heterocycle containing 1, 2 or 3heteroatoms independently selected from N, O and S, 5 memberedunsaturated heterocycle containing 1, 2, 3 or 4 heteroatomsindependently selected from O, N and S, but not more than one of whichis O or S, 6 membered unsaturated heterocycle containing 1, 2 or 3nitrogen atoms, or 8-13 membered unsaturated or partially saturatedheterocycle containing heteroatoms independently selected from O, N andS; any of which rings being optionally substituted by one or more groupsindependently chosen from cyano, halogen, nitro, oxo, hydroxy,C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₁₋₆alkylcarbonyl,C₁₋₆alkoxycarbonyl, carboxy, C₆₋₁₀aryl, C₆₋₁₀aryloxy, C₆₋₁₀arylcarbonyl,N(R^(a))₂ wherein R^(a) is independently selected from hydrogen,C₁₋₆alkyl, C₆₋₁₀aryl, C₁₋₆alkylcarbonyl and C₆₋₁₀arylcarbonyl;C₁₋₆alkylN(R^(a))₂ and (CO)_(d)R^(k) wherein d is 0 or 1 and R^(k) is asdefined above.

In another embodiment, R¹ is a 5 or 6 membered saturated or partiallysaturated heterocycle containing 1, 2 or 3 heteroatoms independentlyselected from N, O and S, 5 membered unsaturated heterocycle containing1, 2, 3 or 4 heteroatoms independently selected from O, N and S, but notmore than one of which is O or S, 6 membered unsaturated heterocyclecontaining 1, 2 or 3 nitrogen atoms, or 8-13 membered unsaturated orpartially saturated heterocycle containing heteroatoms independentlyselected from O, N and S; any of which rings being optionallysubstituted by one or more groups independently chosen from cyano,halogen, nitro, oxo, hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl, carboxy,C₆₋₁₀aryl, C₆₋₁₀aryloxy, C₆₋₁₀arylcarbonyl, N(R^(a))₂ wherein R^(a) isindependently selected from hydrogen, C₁₋₆alkyl, C₆₋₁₀aryl,C₁₋₆alkylcarbonyl and C₆₋₁₀arylcarbonyl; C₁₋₆alkylN(R^(a))₂ and(CO)_(d)R^(k) wherein d is 0 or 1 and R^(k) is as defined above.

In an embodiment, R¹ is an optionally substituted thienyl, isoxazolyl,pyridinyl, benzothienyl, thiazolotriazolyl, dihydrobenzodioxinyl,benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, morpholinyl,tetrahydroisoquinolinyl, indolyl, dibenzo[b,d]furanyl, naphthyridinyl ordihydroquinolinyl.

In an embodiment, R¹ is thienyl, phenylisoxazolyl, pyridinyl,(chloro)(methyl)benzothienyl,(methyl)(trifluoromethyl)thiazolotriazolyl, benzothienyl,dihydrobenzodioxinyl, benzothiazolyl, methoxyquinolinyl, quinolinyl,isoquinolinyl, quinoxalinyl, morpholinyl, tetrahydroisoquinolinyl,methylquinolinyl, indolyl, dibenzo[b,d]furanyl, fluoroquinolinyl,naphthyridinyl or oxodihydroquinolinyl.

In an embodiment, R¹ is 3-thienyl, 3-phenylisoxazol-5-yl, 2-pyridinyl,5-chloro-3-methyl-1-benzothien-2-yl,6-methyl-2-(trifluoromethyl)[1,3]thiazolo[3,2-b][1,2,4]triazol-5-yl,1-benzothien-3-yl, 2,3-dihydro-1,4-benzodioxin-6-yl,2,3-dihydro-1,4-benzodioxin-5-yl, 1,3-benzothiazol-2-yl,1-benzothien-2-yl, 4-methoxyquinolin-2-yl, quinolin-3-yl, quinolin-6-yl,quinolin-2-yl, isoquinolin-3-yl, quinolin-8-yl, quinoxalin-2-yl,morpholin-4-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl,2-methylquinolin-5-yl, quinolin-5-yl, 8-methylquinolin-5-yl,8-methoxyquinolin-5-yl, 1-benzothien-7-yl, 1H-indol-5-yl,dibenzo[b,d]furan-4-yl, quinoxalin-6-yl, 2-thienyl, pyridin-3-yl,pyridin-4-yl, 2-fluoroquinolin-3-yl, quinoxalin-6-yl,8-methoxyquinolin-5-yl, 2-methoxyquinolin-3-yl, 1,8-naphthyridin-2-yl,1,6-naphthyridin-2-yl, 1,6-naphthyridin-8-yl or2-oxo-1,2-dihydroquinolin-3-yl.

In an embodiment, R¹ is 8-13 membered unsaturated or partially saturatedheterocycle containing heteroatoms independently selected from O, N andS; any of which rings being optionally substituted by one or more groupsindependently chosen from cyano, halogen, nitro, oxo, hydroxy,C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₁₋₆alkylcarbonyl,C₁₋₆alkoxycarbonyl, carboxy, C₆₋₁₀aryl, C₆₋₁₀aryloxy, C₆₋₁₀arylcarbonyl,N(R^(a))₂ wherein R^(a) is independently selected from hydrogen,C₁₋₆alkyl, C₆₋₁₀aryl, C₁₋₆alkylcarbonyl and C₆₋₁₀arylcarbonyl;C₁₋₆alkylN(R^(a))₂ and (CO)_(d)R^(k) wherein d is 0 or 1 and R^(k) is asdefined above.

In an embodiment, R¹ is an optionally substituted 8-13 memberedunsaturated or partially saturated heterocycle containing 1, 2, 3 or 4heteroatoms independently selected from O, N and S.

In an embodiments, R¹ is an optionally substituted benzothienyl,thiazolotriazolyl, dihydrobenzodioxinyl, benzothiazolyl, quinolinyl,isoquinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, indonyl,dibenzo[b,d]furanyl, naphthyridinyl or dihydroquinolinyl.

In an embodiment R¹ is an optionally substituted quinolinyl,isoquinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, naphthyridinyl ordihydroquinolinyl.

In an embodiment, R¹ is (chloro)(methyl)benzothienyl,(methyl)(trifluoromethyl)thiazolotriazolyl, benzothienyl,dihydrobenzodioxinyl, benzothiazolyl, methoxyquinolinyl, quinolinyl,isoquinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, methylquinolinyl,indolyl, dibenzo[b,d]furanyl, fluoroquinolinyl, naphthyridinyl oroxodihydroquinolinyl.

In an embodiment, R¹ is 5-chloro-3-methyl-1-benzothien-2-yl,6-methyl-2-(trifluoromethyl)[1,3]thiazolo[3,2-b][1,2,4]triazol-5-yl,1-benzothien-3-yl, 2,3-dihydro-1,4-benzodioxin-6-yl,2,3-dihydro-1,4-benzodioxin-5-yl, 1,3-benzothiazol-2-yl,1-benzothien-2-yl, 4-methoxyquinolin-2-yl, quinolin-3-yl, quinolin-6-yl,quinolin-2-yl, isoquinolin-3-yl, quinolin-8-yl, quinoxalin-2-yl,1,2,3,4-tetrahydroisoquinolin-2-yl, 2-methylquinolin-5-yl,quinolin-5-yl, 8-methylquinolin-5-yl, 8-methoxyquinolin-5-yl,1-benzothien-7-yl, 1H-indol-5-yl, dibenzo[b,d]furan-4-yl,quinoxalin-6-yl, 2-fluoroquinolin-3-yl, quinoxalin-6-yl,8-methoxyquinolin-5-yl, 2-methoxyquinolin-3-yl, 1,8-naphthyridin-2-yl,1,6-naphthyridin-2-yl, 1,6-naphthyridin-8-yl or2-oxo-1,2-dihydroquinolin-3-yl.

In an embodiment, R¹ is 4-methoxyquinolin-2-yl, quinolin-3-yl,quinolin-6-yl, quinolin-2-yl, isoquinolin-3-yl, quinolin-8-yl,quinoxalin-2-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl,2-methylquinolin-5-yl, quinolin-5-yl, 8-methylquinolin-5-yl,8-methoxyquinolin-5-yl, quinoxalin-6-yl, 2-fluoroquinolin-3-yl,quinoxalin-6-yl, 8-methoxyquinolin-5-yl, 2-methoxyquinolin-3-yl,1,8-naphthyridin-2-yl, 1,6-naphthyridin-2-yl, 1,6-naphthyridin-8-yl or2-oxo-1,2-dihydroquinolin-3-yl.

In embodiments, R¹ is quinolinyl, optionally substituted by one or moregroups independently chosen from cyano, halogen, nitro, oxo, hydroxy,C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₁₋₆alkylcarbonyl,C₁₋₆alkoxycarbonyl, carboxy, C₆₋₁₀aryl, C₆₋₁₀aryloxy, C₆₋₁₀arylcarbonyl,N(R^(a))₂ wherein R^(a) is independently selected from hydrogen,C₁₋₆alkyl, C₆₋₁₀aryl, C₁₋₆alkylcarbonyl and C₆₋₁₀arylcarbonyl;C₁₋₆alkylN(R^(a))₂ and (CO)_(d)R^(k) wherein d is 0 or 1 and R^(k) is asdefined above.

In an embodiment R¹ is quinolinyl optionally substituted by C₁₋₆alkoxy,preferably methoxy.

In an embodiment R¹ is 2-methoxyquinolin-3-yl. R² is preferablyhydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₇cycloalkyl, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, N(R^(b))₂, —(C═O)N(R^(c))₂, C₁₋₆alkylS(O)_(w)R^(g) oran optionally substituted ring selected from thienyl, furyl andpyridinyl.

When R² is a ring, it is preferably unsubstituted or substituted by one,two or three groups. In one embodiment the R² ring is unsubstituted.

R² is preferably hydrogen, hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, N(R^(b))₂ or —C═O)—N(R^(c))₂.

R² is preferably hydrogen, hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, N(R^(b))₂ wherein R^(b) is independently selected fromhydrogen, C₁₋₆alkyl, hydroxy and phenyl optionally substituted by amino,hydroxy, nitro, cyano, halogen or C₁₋₆alkyl, —(C═O)—N(R^(c))₂ whereinR^(c) is independently selected from hydrogen and C₁₋₆alkyl or oxazole.

More particularly, R² is hydrogen, hydroxy, C₁₋₆alkyl or N(R^(b))₂. Afurther particular R² group is haloC₁₋₆alkyl. Further particular R²groups are hydroxyC₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₅cycloalkyl,C₁₋₆alkylS(O)_(m)R^(g) and an optionally substituted ring selected fromthienyl, furyl and pyridinyl.

Favourably, R² is C₁₋₄alkyl, hydroxy or N(R^(b))₂. A further favoured R²group is haloC₁₋₄alkyl.

Preferably, when R^(b) is a ring it is unsubstituted or substituted byone, two or three independently selected groups. More particularly, theR^(b) ring is unsubstituted or monosubstituted.

R^(b) is preferably hydrogen, C₁₋₄alkyl, hydroxy or phenyl optionallysubstituted by amino. Further preferred R^(b) groups include C₁₋₄alkoxy,SO₂R^(g) or a benzyl, thiazolyl or thiadiazolyl, the ring beingoptionally substituted by amino. A further preferred R^(b) group isC₁₋₆alkylS(O)_(w)R^(g).

Preferably, R^(b) is methyl, ethyl or trifluoromethyl. A further R^(b)group is amino. Particular R^(b) groups include hydrogen, methyl,hydroxy and aminophenyl. Further particular R^(b) groups include ethyl,isopropyl, methoxy, methylsulfonyl, ethylsulfonyl,trifluoromethylsulfonyl, phenyl, benzyl, thiazolyl and thiadiazolyl.Further particular R^(b) groups include ethoxy and methylthioethyl.

Specific R^(b) groups include hydrogen, methyl, hydroxy and2-aminophenyl. Further specific R^(b) groups include ethyl, isopropyl,methoxy, methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl, phenyl,benzyl, 1,3-thiazol-2-yl and 1,3,4-thiadiazol-2-yl. Further specificR^(b) groups include ethoxy and 2-(methylthio)ethyl.

Thus, particular R² groups are methyl, ethyl, hydroxy, methylamino,hydroxyamino, aminophenylamino, trifluoromethyl, amino, dimethylamino,isopropylamino, phenylamino, benzylamino, methylsulfonylamino,methoxymethylamino, trifluoromethylsulfonylamino, ethylsulfonylamino,ethylamino, thiazolylamino and thiadiazolylamino. Further particular R²groups include butyl, propyl, (methylthio)ethylamino, methoxyamino,ethoxyamino, (methyl)propyl, hydroxymethyl, methoxy, cyclopropyl,methylsulfinylmethyl, thienyl, methylsulfonylmethyl, pyridinyl, furyland aminosulfonylmethyl.

More particular R² groups include methyl, ethyl, hydroxy, methylamino,hydroxyamino and 2-aminophenylamino. Further particular R² groups aretrifluoromethyl, amino, dimethylamino, isopropylamino, phenylamino,benzylamino, methylsulfonylamino, methylmethoxyamino,trifluoromethylsulfonylamino, ethylamino, 1,3-thiazol-2-ylamino and1,3,4-thiadiazol-2-ylamino. Further particular R² groups include butyl,propyl, 2-(methylthio)ethylamino, methoxyamino, ethoxyamino, isopropyl,2-methylpropyl, hydroxymethyl, methoxy, cyclopropyl,methylsulfinylmethyl, 2-thienyl, methylsulfonylmethyl, pyridin-2-yl,2-furyl and aminosulfonylmethyl.

In an embodiment R² is C₁₋₆alkyl, especially methyl or ethyl. In anotherembodiment R² is ethyl.

In an embodiment R³ is hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy,C₃₋₁₀cycloalkyl, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, C₆₋₁₀aryl,C₆₋₁₀arylC₁₋₆alkoxy, a 9-10 membered partially saturated hydrocarbonring; a 4, 5 or 6 membered saturated or partially saturated heterocyclecontaining 1, 2 or 3 heteroatoms independently selected from N, O and S,optionally bridged by a C₁₋₄alkyl group; a 5 membered unsaturatedheterocycle containing 1, 2, 3 or 4 heteroatoms independently selectedfrom N, O and S, but not more than one of which is O or S; a 6 memberedunsaturated heterocycle containing 1, 2 or 3 nitrogen atoms; or a 8, 9,10, 11, 12, 13 or 14 membered saturated, partially saturated orunsaturated heterocycle containing 1, 2, 3 or 4 heteroatomsindependently selected from N, O and S; any of which rings beingoptionally substituted by one or more groups independently chosen from(CH₂)_(m)(CO)_(n)R^(d).

R³ is preferably hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy,C₃₋₁₀cycloalkyl, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, C₆₋₁₀aryl,C₆₋₁₀arylC₁₋₆alkoxy; a 5 or 6 membered saturated or partially saturatedheterocycle containing 1, 2 or 3 heteroatoms independently selected fromN, O and S, optionally bridged by a C₁₋₄alkyl group; a 6 memberedunsaturated heterocycle containing 1, 2 or 3 nitrogen atoms; or a 8-13membered saturated, partially saturated or unsaturated heterocyclecontaining 1, 2, 3 or 4 heteroatoms independently selected from N, O andS; any of which rings being optionally substituted by one or more groupsindependently chosen from R^(d).

In one embodiment, R³ is amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino,C₆₋₁₀aryl; 5 or 6 membered saturated or partially saturated heterocyclecontaining 1, 2 or 3 heteroatoms independently selected from N, O and S,optionally bridged by a C₁₋₄alkyl group; 5 membered unsaturatedheterocycle containing 1, 2, 3 or 4 heteroatoms independently selectedfrom N, O and S, but not more than one of which is O or S; 6 memberedunsaturated heterocycle containing 1, 2 or 3 nitrogen atoms; or 8-10membered saturated, partially saturated or unsaturated heterocyclecontaining 1, 2, 3 or 4 heteroatoms independently selected from N, O orS; any of which rings being optionally substituted by one or more groupsindependently chosen from R^(d).

Particular R³ groups include dimethylamino, phenyl, naphthyl,pyrrolidinyl, piperidyl, azoniabicyclo[2.2.1]heptanyl,azoniabicyclo[2.2.2]octanyl, piperazinyl, morpholinyl, thienyl,thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyridinyl,indolyl, benzothienyl, benzothiadiazolyl, benzoxadiazolyl,dihydrobenzofuryl, dihydrothiazolopyrimidinyl, isoquinolyl,dihydrobenzodioxinyl and dihydrobenzoxazinyl; any of which rings beingoptionally substituted by one or more groups independently chosen fromR^(d). Further particular R³ groups are tert-butoxy, cyclopentyl,methyl, trifluoromethyl, methoxy, methylamino, amino, diethylamino,hydroxy, benzimidazolyl, benzofuranyl, triazolopyrimidinyl,dihydrobenzoxazolyl, dihydroindolyl, dihydroquinazolinyl,dihydrophthalazinyl, indazolyl, quinolinyl, benzisoxazolyl,benzotriazolyl, tetrahydrobetacarbolinyl, dihydroisoindolyl,tetrahydronaphthyridinyl, tetrazolyl, benzyloxy, thiomorpholinyl andazetidinyl; any of which rings being optionally substituted by one ormore groups independently chosen from R^(d). Further particular R³groups are dihydroisochromenyl, dihydrochromenyl, dihydroindenyl,tetrahydroquinolinyl, indenyl, benzothiazolyl, dihydrobenzothiazolyl,tetrahydronaphthyl, imidazothiazolyl, naphthyridinyl,tetrahydroindazolyl, tetrahydrobenzothienyl, hexahydronaphthyridinyl,tetrahydropyridonaphthyridinyl, tetrahydroisoquinolinyl,tetrahydroimidazopyridinyl, tetrahydroimidazopyrazinyl andpyrrolopyridinyl; any of which rings being optionally substituted by oneor more groups independently chosen from (CH₂)_(m)(CO)_(n)R^(d).

In an embodiment, R³ is unsubstituted or substituted by one, two, threeor four groups independently selected from (CH₂)_(m)(CO)_(n)R^(d).

Preferably m is 0, 1 or 2. In one embodiment m is 0.

Preferably n is 0 or 1. In one embodiment n is 0.

Preferably R³ is unsubstituted or substituted by one, two or threegroups selected from R^(d).

Favoured R^(d) groups include halogen, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, carboxy, C₁₋₆alkoxycarbonyl, nitro, aminosulfonyl,(C₁₋₆alkylcarbonyl)amino, morpholinyl, piperazinyl, thiazolyl,pyrazolyl, isoxazolyl and pyridinyl; any of which rings being optionallysubstituted by one or more groups independently chosen from C₁₋₆alkyland haloC₁₋₆alkyl. Further favoured R^(d) groups are oxo, haloC₁₋₆alkyl,phenyl or pyrrolidinyl, any of which rings being optionally substitutedby one or more groups independently chosen from C₁₋₆alkyl andhaloC₁₋₆alkyl. Further favoured R^(d) groups are hydroxy,piperidinespiro, C₆₋₁₀arylC₁₋₆alkoxy, di(C₁₋₆alkyl)amino,C₁₋₆alkylcarbonyl and di(C₁₋₆alkylaminoC₁₋₆alkyl.

Particular R^(d) groups include chlorine, fluorine, cyano, methyl,isopropyl, methoxy, difluoromethoxy, carboxy, nitro, aminosulfonyl,acetylamino, methylpiperazinyl, pyridinyl, methylthiazolyl,(methyl)(trifluoromethyl)pyrazolyl, isoxazolyl, methoxycarbonyl andmorpholinyl. Further particular R^(d) groups are bromine, phenyl, oxo,ethyl, trifluoromethyl and pyrrolidinyl. Further particular R^(d) groupsare hydroxy, piperidinespiro, tert-butyl, ethoxy, benzyloxy,dimethylamino, acetyl, tert-butoxycarbonyl and dimethylaminomethyl.

Specific R^(d) groups include chlorine, fluorine, cyano, methyl,isopropyl, methoxy, difluoromethoxy, carboxy, nitro, aminosulfonyl,acetylamino, 1-methylpiperazin-4-yl, pyridin-2-yl,2-methyl-1,3-thiazol-4-yl, 1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl,isoxazol-3-yl, methoxycarbonyl and morpholin-4-yl. Further specificR^(d) groups include bromine, phenyl, oxo, ethyl, trifluoromethyl andpyrrolidin-1-yl. Further specific R^(d) groups are hydroxy,4′-piperidinespiro, tert-butyl, ethoxy, benzyloxy, dimethylamino,acetyl, tert-butoxycarbonyl, pyridin-3-yl, pyrrolidin-1-yl,morpholin-4-yl, 1-methylpiperazin-4-yl and dimethylaminomethyl.

Thus, particular preferred R³ groups include dimethylamino, phenyl,chlorophenyl, fluorophenyl, difluorophenyl, cyanophenyl,(chloro)(cyano)phenyl, (cyano)(fluoro)phenyl, methoxyphenyl,dimethoxyphenyl, difluoromethoxyphenyl, carboxyphenyl, nitrophenyl,(fluoro)(nitro)phenyl, acetylaminophenyl, (methylpiperazinyl)phenyl,naphthyl, methylpyrrolidinyl, piperidyl, methylpiperidyl,methylpiperazinyl, azoniabicyclo[2.2.1]heptanyl, pyridinylpiperidyl,thienyl, (methylthiazolyl)thienyl,[(methyl)(trifluoromethyl)pyrazolyl]thienyl, isoxazolylthienyl,chlorothienyl, methoxycarbonylthienyl, thiazolyl, dimethylthiazolyl,(acetylamino)(methyl)thiazolyl, dimethylimidazolyl, trimethylpyrazolyl,dimethylisoxazolyl, methylthiadiazolyl, pyridinyl, morpholinylpyridinyl,(methoxy)(methyl)indolyl, benzothienyl, benzothiadiazolyl,benzoxadiazolyl, dihydrobenzofuranyl, dihydrothiazolopyrimidinyl,isoquinolyl, dihydrobenzodioxinyl, (methyl)dihydrobenzoxazinyl,aminosulfonylphenyl, cyanopyridinyl, isopropylpiperidinyl,methylmorpholinyl, azoniabicyclo[2.2.2]octanyl and morpholinyl. Furtherparticularly preferred R³ groups include indolyl, methylindolyl,methoxyindolyl, bromoindolyl, fluoroindolyl, benzimidazolyl,methoxybenzofuranyl, triazolopyrimidinyl, phenylthiazolyl,chlorobenzothienyl, chloroindolyl, oxodihydrobenzoxazolyl,methoxyoxodihydroindolyl, ethylbenzimidazolyl, oxodihydroquinazolinyl,methyloxodihydrophthalazinyl, dichlorophenyl,fluoro(trifluoromethyl)phenyl, methylbenzimidazolyl,(trifluoromethyl)benzimidazolyl, indazolyl, quinolinyl, benzisoxazolyl,benzotriazolyl, cyanoindolyl, tetrahydrobetacarbolinyl, tert-butoxy,dihydroisoindolyl, tetrahydronaphthyridinyl, pyrrolidinyltetrazolyl,cyclopentyl, benzyloxy, methyl, dimethylpyrrolidinyl,dioxothiomorpholinyl, trifluoromethyl, methylazetidinyl,ethylpiperidinyl, methoxy, methylamino, amino, diethylamino and hydroxy.Further particular preferred R³ groups include hydroxyindolyl,(piperidinespiro)dihydroisochromenyl, (piperidinspiro)dihydrochromenyl,chlorobenzimidazolyl, (oxo)dihydrobenzoxazolyl,(piperidinespiro)dihydroindenyl, (oxo)tetrahydroquinolinyl,chloroindazolyl, (ethyl)(methyl)indolyl, (methyl(nitro)indolyl,(methoxy)(methyl)indenyl, (hydroxy)(methyl)indolyl,methoxybenzimidazolyl, dimethylindolyl, methylbenzothiazolyl,(methoxy)(oxo)dihydrobenzoxazolyl, benzothiazolyl,(fluoro)(methyl)indolyl, (tert-butyl)(methyl)indolyl,(ethoxy)(methyl)indolyl, (benzyloxy)(methyl)indolyl,(oxo)dihydrobenzothiazolyl, fluorobenzimidazolyl, tetrahydronaphthyl,(methyl)tetrahydronaphthyridinyl, imidazothiazolyl, benzofuranyl,naphthyridinyl, tetrahydroindazolyl, tetrahydrobenzothienyl,(oxo)dihydroisoindolyl, [(dimethylamino)ethyl](oxo)dihydroisoindolyl,(benzyl)(oxo)hexahydronaphthyridinyl, tetrahydropyridonaphthyridinyl,(acetyl)tetrahydroisoquinolinyl, (methyl)tetrahydroisoquinolinyl,tetrahydroisoquinolinyl,[(tert-butoxy)(oxo)ethyl](methoxy)(methyl)indolyl,(methoxy)(methyl)(pyridinylmethyl)indolyl, (methoxy)dimethylindolyl,(methoxy)(methyl)(pyrrolidinylethyl)indolyl,(methoxy)(methyl)(morpholinylethyl)indolyl, methylbenzisoxazolyl,(dimethylamino)(methyl)indolyl, isoquinolinyl,(methyl)tetrahydroimidazopyridinyl, methylbenzothienyl,(carboxymethyl)(methoxy)(methyl)indolyl,(methoxy)(methyl)[(methylpiperazinyl)(oxo)ethyl]indolyl,(methyl)tetrahydroimidazopyrazinyl,[(dimethylamino)methyl](methyl)indolyl, tetrafluoroindolyl,(fluoro)(methyl)indolyl, pyrrolopyridinyl, (methoxy)pyrrolopyridinyl,imidazolyl, acetylpiperazinyl, (dimethylglycyl)azetidinyl,(methoxyethyl)azetidinyl and methoxyazetidinyl.

Specific R³ groups are dimethylamino, phenyl, 4-chlorophenyl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl,2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-chloro-4-cyanophenyl,3-cyano-4-fluorophenyl, 3-methoxyphenyl, 4-methoxyphenyl,2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-difluoromethoxyphenyl,4-difluoromethoxyphenyl, 4-carboxyphenyl, 2-nitrophenyl, 3-nitrophenyl,4-nitrophenyl, 3-fluoro-4-nitrophenyl, 4-acetylaminophenyl,4-(1-methylpiperazin-4-yl)phenyl, 2-naphthyl, 1-methylpyrrolidin-3-yl,piperidin-1-yl, 1-methylpiperidin-2-yl, 1-methylpiperidin-3-yl,1-methylpiperidin-4-yl, 1-methylpiperazin-4-yl,azoniabicyclo[2.2.1]heptan-2-yl, 1-pyridin-2-ylpiperidin-3-yl,2-thienyl, 5-(2-methyl-1,3-thiazol-4-yl)-2-thienyl,5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl,5-isoxazol-3-yl-2-thienyl, 5-chloro-2-thienyl,2-(methoxycarbonyl)-3-thienyl, 1,3-thiazol-5-yl,2,4-dimethyl-1,3-thiazol-5-yl,2-(acetylamino)-4-methyl-1,3-thiazol-5-yl,1,2-dimethyl-1H-imidazol-4-yl, 1,3,5-trimethyl-1H-pyrazol-4-yl,3,5-dimethylisoxazol-4-yl, 4-methyl-1,2,3-thiadiazol-5-yl, pyridin-3-yl,2-morpholin-4-ylpyridin-5-yl, 5-methoxy-2-methyl-1H-indol-3-yl,benzothien-3-yl, 2,1,3-benzothiadiazol-5-yl, 2,1,3-benzoxadiazol-4-yl,2,3-dihydro-1-benzofuran-5-yl,6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl, isoquinol-5-yl,2,3-dihydro-1,4-benzodioxin-6-yl,4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl, pyridin-4-yl,4-aminosulfonylphenyl, 2-cyanopyridin-5-yl, 1-isopropylpiperidin-3-yl,4-methylmorpholin-2-yl, azoniabicyclo[2.2.2]octan-4-yl andmorpholin-4-yl. Further specific R³ groups are 1H-indol-3-yl,2-methyl-1H-indol-3-yl, 5-methoxy-1H-indol-3-yl, 5-bromo-1H-indol-3-yl,5-fluoro-1H-indol-3-yl, 1H-benzimidazol-1-yl,7-methoxy-1-benzofuran-2-yl, 5-methoxy-1H-indol-2-yl,5-fluoro-1H-indol-2-yl, [1,2,4]triazolo[1,5-a]pyrimidin-6-yl,4-phenyl-1,3-thiazol-2-yl, 5-chloro-1-benzothien-3-yl,4-chloro-1H-indol-3-yl, 2-oxo-1,3-benzoxazol-3(2H)-yl,5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl,6-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl, 2-ethyl-1H-benzimidazol-1-yl,1-naphthyl, 2-oxoquinazolin-1-(2H)-yl,4-methyl-1-oxophthalazin-2(1H)-yl, 2,4-dichlorophenyl,2-fluoro-6-(trifluoromethyl)phenyl, 2,6-dichlorophenyl,2-fluoro-3-(trifluoromethyl)phenyl, 2-methyl-1H-benzimidazol-1-yl,2-(trifluoromethyl)-1H-benzimidazol-1-yl, 1H-indazol-1-yl,quinolin-3-yl, 1,2-benzisoxazol-3-yl, 2-methyl-1H-indol-1-yl,1H-1,2,3-benzotriazol-1-yl, 5-cyano-1H-indol-1-yl,2,3,4,9-tetrahydro-1H-beta-carbolin-4-yl, tert-butoxy,2,3-dihydro-1H-isoindol-2-yl, 1,2,3,4-tetrahydro-1,8-naphthyridin-5-yl,5-pyrrolidin-1-yl-2H-tetrazol-2-yl, cyclopentyl, benzyloxy, methyl,1,3-dimethylpyrrolidin-3-yl, 1,1-dioxothiomorpholin-4-yl,trifluoromethyl, 1-methylazetidin-3-yl, 1-ethylpiperidin-3-yl, methoxy,methylamino, amino, diethylamino, 5-cyano-1H-indol-3-yl and hydroxy.Further specific R³ groups are 1-methyl-1H-indol-3-yl,6-fluoro-1H-indol-3-yl, 5-chloro-1H-indol-3-yl, 1H-indol-2-yl,5-hydroxy-1H-indol-3-yl,1,4′-piperidinespiro-3,4-dihydroisochromen-3-yl,2,4-piperidinespiro-3,4-dihydrochromen-4-yl,5-chloro-1H-benzimidazol-2-yl, 2-oxo-1,3-benzoxazol-3(2H)-yl,2H-indazol-2-yl, 1,4′-piperidinespiro-2,3-dihydroinden-3-yl,2-oxo-1,2,3,4-tetrahydroquinolin-4-yl, 5-chloro-1H-indazol-3-yl,2-ethyl-5-methyl-1H-indol-3-yl, 2-ethyl-6-methyl-1H-indol-3-yl,2-methyl-5-nitro-1H-indol-3-yl, 5-methoxy-2-methyl-1H-inden-3-yl,5-hydroxy-2-methyl-1H-indol-3-yl, 5-methoxy-1H-benzimidazol-2-yl,2,5-dimethyl-1H-indol-3-yl, 1H-benzimidazol-2-yl,6-methoxy-1H-indol-3-yl, 1H-indol-6-yl, 2-methyl-1,3-benzothiazol-5-yl,5-methoxy-2-oxo-1,3-benzoxazol-3(2H)-yl, 7-methoxy-1H-indol-3-yl,1,3-benzothiazol-2-yl, 7-fluoro-2-methyl-1H-indol-3-yl,5-ethyl-2-methyl-1H-indol-3-yl, 5-tert-butyl-2-methyl-1H-indol-3-yl,5-ethoxy-2-methyl-1H-indol-3-yl, 5-(benzyloxy)-2-methyl-1H-indol-3-yl,1H-indol-1-yl, 2-oxo-1,3-benzothiazol-3(2H)-yl, quinolin-5-yl,6-fluoro-1H-benzimidazol-2-yl, 5,6,7,8-tetrahydronaphthalen-1-yl,3-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl,imidazo[2,1-b][1,3]thiazol-6-yl, 1-benzofuran-5-yl, 1-benzothien-2-yl,1,8-naphthyridin-2-yl, 1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl,4,5,6,7-tetrahydro-1H-indazol-3-yl,4,5,6,7-tetrahydro-1-benzothien-3-yl,1-oxo-1,3-dihydro-2H-isoindol-2-yl,2-[2-(dimethylamino)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl,6-benzyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridin-3-yl,6,7,8,9-tetrahydropyrido[2,3-b]-1,6-naphthyridin-7-yl,2-acetyl-1,2,3,4-tetrahydroisoquinolin-1-yl,2-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl,1,2,3,4-tetrahydroisoquinolin-2-yl,1-(2-tert-butoxy-2-oxoethyl)-5-methoxy-2-methyl-1H-indol-3-yl,5-methoxy-2-methyl-1-(pyridin-3-ylmethyl)-1H-indol-3-yl,5-methoxy-1,2-dimethyl-1H-indol-3-yl,5-methoxy-2-methyl-1-(2-pyrrolidin-1-ylethyl)-1H-indol-3-yl,5-methoxy-2-methyl-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl,5-methyl-1,2-benzisoxazol-3-yl,5-(dimethylamino)-2-methyl-1H-indol-3-yl, 6-methoxy-1-benzofuran-3-yl,quinolin-6-yl, isoquinolin-6-yl,5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl,5-methyl-1-benzothien-3-yl,1-(carboxymethyl)-5-methoxy-2-methyl-1H-indol-3-yl,5-methoxy-2-methyl-1-[2-(1-methylpiperazin-4-yl)-2-oxoethyl]-1H-indol-3-yl,7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl,5-[(dimethylamino)methyl]-2-methyl-1H-indol-3-yl,4,5,6,7-tetrafluoro-1H-indol-3-yl, 5-fluoro-2-methyl-1H-indol-3-yl,1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[3,2-c]pyridin-3-yl,5-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl,2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl, 1H-imidazol-1-yl,4-acetylpiperazin-1-yl, 1-(N,N-dimethylglycyl)azetidin-3-yl,1-(2-methoxyethyl)azetidin-3-yl, 3-methoxyazetidin-1-yl and1-azoniabicyclo[2.2.2]octan-3-yl.

In an embodiment R³ is azoniabicyclo[2.2.1]heptanyl,azoniabicyclo[2.2.2]octanyl, thiazolyl, pyrazolyl, isoxazolyl,thiadiazolyl, benzothienyl, benzothiadiazolyl, benzoxadiazolyl,dihydrobenzofuryl, dihydrothiazolopyrimidinyl, dihydrobenzodioxinyl,dihydrobenzoxazinyl, benzimidazolyl, triazolopyrimidinyl,dihydrobenzoxazolyl, dihydroindolyl, dihydroquinazolinyl,dihydrophthalazinyl, indazolyl, benzisoxazolyl, benzotriazolyl,tetrahydrobetacarbolinyl, dihydroisoindolyl, tetrahydronaphthyridinyl,tetrazolyl, thiomorpholinyl, azetidinyl, dihydroisochromenyl,dihydrochromenyl, tetrahydroquinolinyl, indenyl, dihydrobenzothiazolyl,imidazothiazolyl, naphthyridinyl, tetrahydroindazolyl,tetrahydrobenzothienyl, hexahydronaphthyridinyl,tetrahydropyridonaphthyridinyl, tetrahydroisoquinolinyl,tetrahydroimidazopyridinyl, tetrahydroimidazopyrazinyl orpyrrolopyridinyl; any of which rings being optionally substituted by oneor more groups independently chosen from (CH₂)_(m)(CO)_(n)R^(d).

Particular preferred R³ groups azoniabicyclo[2.2.1]heptanyl, thiazolyl,dimethylthiazolyl, (acetylamino)(methyl)thiazolyl, trimethylpyrazolyl,dimethylisoxazolyl, methylthiadiazolyl, benzothienyl, benzothiadiazolyl,benzoxadiazolyl, dihydrobenzofuranyl, dihydrothiazolopyrimidinyl,dihydrobenzodioxinyl, (methyl)dihydrobenzoxazinyl,azoniabicyclo[2.2.2]octanyl, benzimidazolyl, triazolopyrimidinyl,phenylthiazolyl, chlorobenzothienyl, oxodihydrobenzoxazolyl,methoxyoxodihydroindolyl, ethylbenzimidazolyl, oxodihydroquinazolinyl,methyloxodihydrophthalazinyl, methylbenzimidazolyl,(trifluoromethyl)benzimidazolyl, indazolyl, benzisoxazolyl,benzotriazolyl, tetrahydrobetacarbolinyl, dihydroisoindolyl,tetrahydronaphthyridinyl, pyrrolidinyltetrazolyl, dioxothiomorpholinyl,methylazetidinyl, (piperidinespiro)dihydroisochromenyl,(piperidinspiro)dihydrochromenyl, chlorobenzimidazolyl,(oxo)dihydrobenzoxazolyl, (oxo)tetrahydroquinolinyl, chloroindazolyl,(methoxy)(methyl)indenyl, methoxybenzimidazolyl,(methoxy)(oxo)dihydrobenzoxazolyl, (oxo)dihydrobenzothiazolyl,fluorobenzimidazolyl, (methyl)tetrahydronaphthyridinyl,imidazothiazolyl, naphthyridinyl, tetrahydroindazolyl,tetrahydrobenzothienyl, (oxo)dihydroisoindolyl,[(dimethylamino)ethyl]dihydroisoindolyl,(benzyl)(oxo)hexahydronaphthyridinyl, tetrahydropyridonaphthyridinyl,(acetyl)tetrahydroisoquinolinyl, (methyl)tetrahydroisoquinolinyl,tetrahydroisoquinolinyl, methylbenzisoxazolyl,(methyl)tetrahydroimidazopyridinyl, methylbenzothienyl,(methyl)tetrahydroimidazopyrazinyl, pyrrolopyridinyl,(methoxy)pyrrolopyridinyl, (dimethylglycyl)azetidinyl,(methoxyethyl)azetidinyl and methoxyazetidinyl.

In an embodiment, R³ is azoniabicyclo[2.2.1]heptan-2-yl,1,3-thiazol-5-yl, 2,4-dimethyl-1,3-thiazol-5-yl,2-(acetylamino)-4-methyl-1,3-thiazol-5-yl,1,3,5-trimethyl-1H-pyrazol-4-yl, 3,5-dimethylisoxazol-4-yl,4-methyl-1,2,3-thiadiazol-5-yl, benzothien-3-yl,2,1,3-benzothiadiazol-5-yl, 2,1,3-benzoxadiazol-4-yl,2,3-dihydro-1-benzofuran-5-yl,6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl,2,3-dihydro-1,4-benzodioxin-6-yl,4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl,azoniabicyclo[2.2.2]octan-4-yl, 1H-benzimidazol-1-yl,[1,2,4]triazolo[1,5-a]pyrimidin-6-yl, 4-phenyl-1,3-thiazol-2-yl,5-chloro-1-benzothien-3-yl, 2-oxo-1,3-benzoxazol-3(2H)-yl,5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl,6-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl, 2-ethyl-1H-benzimidazol-1-yl,2-oxoquinazolin-1-(2H)-yl, 4-methyl-1-oxophthalazin-2(1H)-yl,2-methyl-1H-benzimidazol-1-yl, 2-(trifluoromethyl)-1H-benzimidazol-1-yl,1H-indazol-1-yl, 1,2-benzisoxazol-3-yl, 1H-1,2,3-benzotriazol-1-yl,2,3,4,9-tetrahydro-1H-beta-carbolin-4-yl, 2,3-dihydro-1H-isoindol-2-yl,1,2,3,4-tetrahydro-1,8-naphthyridin-5-yl,5-pyrrolidin-1-yl-2H-tetrazol-2-yl, 1,1-dioxothiomorpholin-4-yl,1-methylazetidin-3-yl, 1,4′-piperidinespiro-3,4-dihydroisochromen-3-yl,2,4-piperidinespiro-3,4-dihydrochromen-4-yl,5-chloro-1H-benzimidazol-3-yl, 2-oxo-1,3-benzoxazol-3(2H)-yl,2H-indazol-2-yl, 1,4′-piperidinespiro-2,3-dihydroinden-3-yl,2-oxo-1,2,3,4-tetrahydroquinolin-4-yl, 5-chloro-1H-indazol-3-yl,5-methoxy-2-methyl-1H-inden-3-yl, 5-methoxy-1H-benzimidazol-2-yl,1H-benzimidazol-2-yl, 5-methoxy-2-oxo-1,3-benzoxazol-3(2H)-yl,2-oxo-1,3-benzothiazol-3(2H)-yl, 6-fluoro-1H-benzimidazol-2-yl,5,6,7,8-tetrahydronaphthalen-1-yl,3-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl,imidazo[2,1-b][1,3]thiazol-6-yl, 1-benzothien-2-yl,1,8-naphthyridin-2-yl, 1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl,4,5,6,7-tetrahydro-1H-indazol-3-yl,4,5,6,7-tetrahydro-1-benzothien-3-yl,1-oxo-1,3-dihydro-2H-isoindol-2-yl,2-[2-(dimethylamino)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl,6-benzyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridin-3-yl,6,7,8,9-tetrahydropyrido[2,3-b]-1,6-naphthyridin-7-yl,2-acetyl-1,2,3,4-tetrahydroisoquinolin-1-yl,2-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl,1,2,3,4-tetrahydroisoquinolin-2-yl, 5-methyl-1,2-benzisoxazol-3-yl,5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl,5-methyl-1-benzothien-3-yl,7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl,1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[3,2-c]pyridin-3-yl,5-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl,2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl,1-(N,N-dimethylglycyl)azetidin-3-yl, 1-(2-methoxyethyl)azetidin-3-yl,3-methoxyazetidin-1-yl or 1-azoniabicyclo[2.2.2]octan-3-yl.

In an embodiment, R³ is azetidinyl, optionally substituted by one ormore groups independently chosen from (CH₂)_(m)(CO)_(n)R^(d).Preferably, the optional substituent is C₁₋₆alkyl, especially methyl.

In an embodiment, R³ is 1-methylazetidin-3-yl,1-(N,N-dimethylglycyl)azetidin-3-yl, 1-(2-methoxyethyl)azetidin-3-yl or3-methoxyazetidin-1-yl.

In an embodiment, R³ is 1-methylazetidin-3-yl.

R⁴ is preferably hydrogen.

R⁵ is preferably C₁₋₆alkyl, especially methyl. A further preferred R⁵group is hydrogen.

Preferably, R⁶ and R⁸ are independently hydrogen, C₁₋₆alkyl or anoptionally substituted 5 or 6 membered saturated or partially saturatedheterocycle containing 1, 2 or 3 heteroatoms independently selected fromN, O and S; or R⁶ and R⁸ together form an oxo group.

More particularly, R⁶ is hydrogen, C₁₋₄alkyl or morpholinyl and R⁸ ishydrogen or C₁₋₄alkyl; or R⁶ and R⁸ together form an oxo group.

Specifically, R⁶ is hydrogen, methyl or morpholin-4-yl and R⁸ ishydrogen or methyl; or R⁶ and R⁸ together form an oxo group.

In one embodiment, R⁶ is hydrogen, C₁₋₆alkyl or a 5 or 6 memberedsaturated or partially saturated heterocycle containing 1, 2 or 3heteroatoms independently selected from N, O or S, optionallysubstituted by C₁₋₆alkyl.

Particular R⁶ groups include hydrogen, methyl and morpholinyl. Mostpreferably R⁶ is hydrogen, methyl or morpholin-4-yl.

In one embodiment R⁶ is hydrogen.

R⁸ is preferably hydrogen or C₁₋₆alkyl. More particularly, R⁸ ishydrogen or methyl.

In one embodiment R⁸ is hydrogen.

In an embodiment, R⁶ and R⁸ together form an oxo group.

In an embodiment R^(a) is hydrogen, C₁₋₆alkyl or C₁₋₆alkylcarbonyl.Preferably, R^(a) is hydrogen, methyl or acetyl.

In an embodiment R^(c) is hydrogen or methyl.

In an embodiment R^(e) is hydrogen, C₁₋₆alkyl or C₁₋₆alkylcarbonyl.Preferably, R^(e) is hydrogen, methyl or acetyl.

In an embodiment R^(h) is hydrogen, C₁₋₆alkyl or C₆₋₁₀arylC₁₋₆alkyl.Preferably, R^(h) is methyl or benzyl.

In an embodiment R^(k) is NHSO₂R^(g), pyrazolyl, piperidinyl,morpholinyl or tetrazolyl, any of which rings being optionallysubstituted by C₁₋₆alkyl, especially methyl. Preferably, R^(k) isdimethylpyrazolyl, piperidinyl, morpholinyl, pyrazolyl, tetrazolyl or(methylsulfonyl)amino.

Preferably, the α1 carbon asymmetric center of the compounds of thepresent invention has the stereochemical configuration of S. In oneembodiment the α1 carbon asymmetric center has the stereochemicalconfiguration of R.

The present invention also provides compounds of formula II:

wherein:R¹, R³, R⁵, R⁶, R⁸, X, p and t are as defined for formula I;D is absent, CH₂, CH₂CH₂ or CH═CH;A represents CH or N;Y represents NR^(e), O or S;Z represents N or CRC;R⁷ represents C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxy, N(R^(b))₂,hydroxyC₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₇cycloalkyl, C₁₋₆alkylS(O)_(m)R^(g),thienyl, furyl or pyridinyl;R^(b) represents hydrogen, C₁₋₄alkyl, hydroxy, C₁₋₄alkoxy,C₁₋₆alkylS(O)_(w)R^(g), SO₂R^(g), phenyl, benzyl, thiazolyl orthiadiazolyl, any of which rings being optionally substituted by amino;R^(e) represents hydrogen or C₁₋₆alkyl;R^(f) represents hydrogen, C₁₋₆alkyl or C₆₋₁₀aryl optionally substitutedby up to two groups selected from halogen, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkyl or haloC₁₋₆alkoxy;R^(g) is C₁₋₆alkyl, haloC₁₋₆alkyl, amino, C₁₋₆alkylamino ordi(C₁₋₆alkyl)amino;w is 0, 1 or 2;or a pharmaceutically acceptable salt or tautomer thereof.

In one embodiment:

D is absent;

R⁷ is C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxy, or N(R^(b))₂;

R^(b) is hydrogen, C₁₋₄alkyl, hydroxy, C₁₋₄alkoxy, SO₂R^(g), phenyl,benzyl, thiazolyl or thiadiazolyl, any of which rings being optionallysubstituted by amino;

R¹ is C₁₋₆alkyl or haloC₁₋₆alkyl;

or a pharmaceutically acceptable salt or tautomer thereof.

In an embodiment of the previous embodiment:

R⁷ is C₁₋₆alkyl, hydroxy or N(R^(b))₂;

R⁸ is hydrogen; and

R^(b) is hydrogen, C₁₋₄alkyl, hydroxy or phenyl optionally substitutedby amino.

A favoured class of compounds of the present invention have thestereochemical configuration of formula III:

wherein R¹, R³, R⁵, R⁶, R⁷, R⁸, A, D, X, Y, Z, p and t are as definedfor formula II.

The preferred identities with reference to formula II and III are asdefined previously mutatis mutandis.

In one embodiment:

D is absent;

R⁷ is C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxy, or N(R^(b))₂;

R^(b) is hydrogen, C₁₋₄alkyl, hydroxy, C₁₋₄alkoxy, SO₂R^(g), phenyl,benzyl, thiazolyl or thiadiazolyl, any of which rings being optionallysubstituted by amino;

R^(g) is C₁₋₆alkyl or haloC₁₋₆alkyl;

or a pharmaceutically acceptable salt or tautomer thereof.

In an embodiment of the previous embodiment:

R⁷ is C₁₋₆alkyl, hydroxy or N(R^(b))₂;

R⁸ is hydrogen; and

R^(b) is hydrogen, C₁₋₄alkyl, hydroxy or phenyl optionally substitutedby amino.

For the avoidance of doubt, R¹ may be attached to any substitutableposition of the ring.

In one embodiment D is absent.

In one embodiment A is N, Y is NR^(e) or O and Z is N or CR^(f).

In another embodiment A is N, Y is NR^(e) and Z is CR^(f).

In yet another embodiment A is CH, Y is S and Z is CR^(f).

In another embodiment A and Z are both N and Y is NR^(e).

In yet another embodiment Y is O.

R¹ is preferably phenyl, naphthyl, thienyl, isoxazolyl, pyridinyl,benzothienyl or thiazolotriazolyl, optionally substituted by one or twogroups independently selected from cyano, bromine, chlorine, fluorine,methyl, trifluoromethyl, methoxy, difluoromethoxy or phenyl. Furtherpreferred R¹ groups are hydrogen and optionally substituteddihydrobenzodioxinyl, benzothiazolyl, quinolinyl or isoquinolinyl.Further preferred R¹ groups include hydroxy, (benzyl)(methyl)amino,dimethylamino, methoxycarbonyl, acetyl, cyclohexyl, bromine andoptionally substituted quinoxalinyl, morpholinyl,tetrahydroisoquinolinyl, indolyl, dibenzo[b,d]furanyl, naphthyridinyl ordihydroquinolinyl.

R³ is preferably dimethylamino, phenyl, napthyl, pyrrolidinyl,piperidyl, azoniabicyclo[2.2.1]heptanyl, azoniabicyclo[2.2.2]octanyl,piperazinyl, morpholinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, thiadiazolyl, pyridinyl, indolyl, benzothienyl,benzothiadiazolyl, benzoxadiazolyl, dihydrobenzofuryl,dihydrothiazolopyrimidinyl, isoquinolyl, dihydrobenzodioxinyl anddihydrobenzoxazinyl, any of which rings being optionally substituted byone, two or three groups independently selected from chlorine, fluorine,methyl, isopropyl, cyano, methoxy, difluoromethoxy, carboxy, nitro,aminosulfonyl, acetylamino, methylpiperazinyl, pyridinyl,methylthiazolyl, (methyl)(trifluoromethyl)pyrazolyl, isoxazolyl,methoxycarbonyl and morpholinyl. Further optional substituents on therings include bromo, phenyl, oxo, ethyl, trifluoromethyl andpyrrolidinyl. Further optional substituents on the rings includehydroxy, piperidinespiro, tert-butyl, ethoxy, benzyloxy,dimethylaminoethyl, benzyl, acetyl (tert-butoxycarbonyl)methyl,pyridinylmethyl, pyrrolidinylethyl, morpholinylethyl, dimethylamino,carboxymethyl, [(methylpiperazinyl)carbonyl]methyl, dimethylaminomethyl,(dimethylaminomethyl)carbonyl and methoxyethyl. Further preferred R³groups are tert-butoxy, cyclopentyl, methyl, trifluoromethyl, methoxy,methylamino, amino, diethylamino, hydroxy or an optionally substitutedring selected from benzimidazolyl, benzofuranyl, triazolopyrimidinyl,dihydrobenzoxazolyl, dihydroindolyl, dihydroquinazolinyl,dihydrophthalazinyl, indazolyl, quinolinyl, benzisoxazolyl,benzotriazolyl, tetrahydrobetacarbolinyl, dihydroisoindolyl,tetrahydronaphthyridinyl, tetrazolyl, benzyloxy, thiomorpholinyl andazetidinyl, the optional substituents defined above. Further preferredR³ groups are optionally substituted rings selected fromdihydroisochromenyl, dihydrochromenyl, dihydroindenyl,tetrahydroquinolinyl, indenyl, benzothiazolyl, dihydrobenzothiazolyl,tetrahydronaphthyl, imidazothiazolyl, naphthyridinyl,tetrahydroindazolyl, tetrahydrobenzothienyl, hexahydronaphthyridinyl,tetrahydropyridonaphthyridinyl, tetrahydroisoquinolinyl,tetrahydroimidazopyridinyl, tetrahydroimidazopyrazinyl andpyrrolopyridinyl, the optional substituents defined above.

R⁵ is preferably methyl. A further preferred R⁵ group is hydrogen.

R⁶ is preferably hydrogen, methyl or morpholinyl.

R⁷ is preferably methyl, ethyl, hydroxy or N(R^(b))₂. A furtherpreferred R⁷ group is trifluoromethyl. Further preferred R⁷ groups arebutyl, propyl, isopropyl, (methyl)propyl, hydroxymethyl, methoxy,cyclopropyl, methylsulfinylmethyl, thienyl, methylsulfonylmethyl,pyridinyl, furyl and aminosulfonylmethyl.

In an embodiment R⁷ is C₁₋₆alkyl.

In another embodiment R⁷ is methyl or ethyl.

R^(b) is preferably hydrogen, methyl, hydroxy or aminophenyl. Furtherpreferred R^(b) groups include ethyl, isopropyl, methoxy,methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl, phenyl, benzyl,thiazolyl and thiadiazolyl. Further preferred R^(b) groups aremethylthioethyl and ethoxy.

Thus, particular preferred R⁷ groups include methyl, ethyl, hydroxy,methylamino, hydroxyamino and (aminophenyl)amino. Further particular R⁷groups include trifluoromethyl, amino, dimethylamino, isopropylamino,phenylamino, benzylamino, methylsulfonylamino, methoxymethylamino,trifluoromethylsulfonylamino, ethylsulfonylamino, ethylamino,thiazolylamino and thiadiazolylamino. Further particular R⁷ groupsinclude butyl, propyl, (methylthio)ethylamino, methoxyamino,ethoxyamino, propyl, (methyl)propyl, hydroxymethyl, methoxy,cyclopropyl, methylsulfinylmethyl, thienyl, methylsulfonylmethyl,pyridinyl, furyl and aminosulfonylmethyl.

R^(e) is preferably hydrogen or methyl.

R^(f) is preferably hydrogen, C₁₋₆alkyl or C₆₋₁₀aryl. More particularlyR^(f) is hydrogen, methyl or phenyl. A further particular R^(f) group isnaphthyl, especially 2-naphthyl.

R^(g) is preferably methyl, ethyl or trifluoromethyl. A further R^(g)group is amino.

Preferably w is 1 or 2

The present invention also provides intermediates of compounds offormula I represented by formula IA:

wherein R^(p) is R⁴ or an appropriate protecting group such as Boc;R¹, R², R⁴, Het and q are as defined above;or a pharmaceutically acceptable salt or tautomer thereof.

In one embodiment D is absent.

In one embodiment R^(p) is hydrogen or Boc.

The preferred identities with reference to formula IA are as definedpreviously mutatis mutandis.

The present invention also provides compounds of formula IB:

wherein D, R² and X are as defined above for formula I;

R¹ is a 8-13 membered unsaturated or partially saturated heterocyclecontaining heteroatoms independently selected from O, N and S; any ofwhich rings being optionally substituted by one or more groupsindependently chosen from cyano, halogen, nitro, oxo, hydroxy,C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₁₋₆alkylcarbonyl,C₁₋₆alkoxycarbonyl, carboxy, C₆₋₁₀aryl, C₆₋₁₀aryloxy, C₆₋₁₀arylcarbonyl,N(R^(a))₂ wherein R^(a) is independently selected from hydrogen,C₁₋₆alkyl, C₆₋₁₀aryl, C₁₋₆alkylcarbonyl and C₆₋₁₀arylcarbonyl;C₁₋₆alkylN(R^(a))₂ and (CO)_(d)R^(k) wherein d is 0 or 1;

R^(k) is C₁₋₆alkoxy, NHSO₂R^(g), 5 or 6 membered saturated or partiallysaturated heterocycle containing 1, 2 or 3 heteroatoms independentlyselected from N, O and S or a 5 membered unsaturated heterocyclecontaining 1, 2, 3 or 4 heteroatoms independently selected from N, O andS, but not more than one of which is O or S; any of which rings beingoptionally substituted by one or more groups independently selected fromhalogen and C₁₋₆alkyl;

R^(g) is C₁₋₆alkyl, haloC₁₋₆alkyl, amino, C₁₋₆alkylamino ordi(C₁₋₆alkyl)amino;

R³ is azoniabicyclo[2.2.1]heptanyl, azoniabicyclo[2.2.2]octanyl,thiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, benzothienyl,benzothiadiazolyl, benzoxadiazolyl, dihydrobenzofuryl,dihydrothiazolopyrimidinyl, dihydrobenzodioxinyl, dihydrobenzoxazinyl,benzimidazolyl, triazolopyrimidinyl, dihydrobenzoxazolyl,dihydroindolyl, dihydroquinazolinyl, dihydrophthalazinyl, indazolyl,benzisoxazolyl, benzotriazolyl, tetrahydrobetacarbolinyl,dihydroisoindolyl, tetrahydronaphthyridinyl, tetrazolyl,thiomorpholinyl, azetidinyl, dihydroisochromenyl, dihydrochromenyl,tetrahydroquinolinyl, dihydrobenzothiazolyl, imidazothiazolyl,naphthyridinyl, tetrahydroindazolyl, tetrahydrobenzothienyl,hexahydronaphthyridinyl, tetrahydropyridonaphthyridinyl,tetrahydroisoquinolinyl, tetrahydroimidazopyridinyl,tetrahydroimidazopyrazinyl or pyrrolopyridinyl; any of which rings beingoptionally substituted by one or more groups independently chosen from(CH₂)_(m)(CO)_(n)R^(d);

m is 0, 1, 2 or 3;

n is 0, 1 or 2; and

R^(d) is halogen, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, carboxy,C₁₋₆alkoxycarbonyl, nitro, aminosulfonyl, (C₁₋₆alkylcarbonyl)amino,morpholinyl, piperazinyl, thiazolyl, pyrazolyl, isoxazolyl, pyridinyl,oxo, haloC₁₋₆alkyl, phenyl or pyrrolidinyl, hydroxy, piperidinespiro,C₆₋₁₀arylC₁₋₆alkoxy, di(C₁₋₆alkyl)amino, C₁₋₆alkylcarbonyl ordi(C₁₋₆alkylaminoC₁₋₆alkyl; any of which rings being optionallysubstituted by one or more groups independently chosen from C₁₋₆alkyland haloC₁₋₆alkyl;

or a pharmaceutically acceptable salt or tautomer thereof.

The preferred identities with reference to formula IIB are thepreviously defined embodiments for formulae I, II and III, which fallwithin the scope of formula IB.

In an embodiment, R¹ is an optionally substituted 8-13 memberedunsaturated or partially saturated heterocycle containing 1, 2, 3 or 4heteroatoms independently selected from O, N and S.

In an embodiment:

R¹ is an optionally substituted benzothienyl, thiazolotriazolyl,dihydrobenzodioxinyl, benzothiazolyl, quinolinyl, isoquinolinyl,quinoxalinyl, tetrahydroisoquinolinyl, indonyl, dibenzo[b,d]furanyl,naphthyridinyl or dihydroquinolinyl; and

R³ is an optionally substituted azetidinyl.

In an embodiment:

R¹ is an optionally substituted quinolinyl, isoquinolinyl, quinoxalinyl,tetrahydroisoquinolinyl, naphthyridinyl or dihydroquinolinyl; and

R³ is an optionally substituted azetidinyl

In an embodiment:

R¹ is 2-methoxyquinolin-3-yl; and

R³ is 1-methylazetidin-3-yl.

Preferably R² is C₁₋₆alkyl, especially methyl or ethyl.

Preferably D is a direct bond.

Preferably X is C.

The present invention also includes within its scope N-oxides of thecompounds of formula I above. In general, such N-oxides may be formed onany available nitrogen atom. The N-oxides may be formed by conventionalmeans, such as reacting the compound of formula I with oxone in thepresence of wet alumina.

The present invention includes within its scope prodrugs of thecompounds of formula I above. In general, such prodrugs will befunctional derivatives of the compounds of formula I which are readilyconvertible in vivo into the required compound of formula I.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

A prodrug may be a pharmacologically inactive derivative of abiologically active substance (the “parent drug” or “parent molecule”)that requires transformation within the body in order to release theactive drug, and that has improved delivery properties over the parentdrug molecule. The transformation in vivo may be, for example, as theresult of some metabolic process, such as chemical or enzymatichydrolysis of a carboxylic, phosphoric or sulphate ester, or reductionor oxidation of a susceptible functionality.

The present invention includes within its scope solvates of thecompounds of formula I and salts thereof, for example, hydrates.

The compounds of the present invention may have asymmetric centers,chiral axes, and chiral planes (as described in: E. L. Eliel and S. H.Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York,1994, pages 1119-1190), and occur as racemates, racemic mixtures, and asindividual diastereomers, with all possible isomers and mixturesthereof, including optical isomers, all such stereoisomers beingincluded in the present invention. In addition, the compounds disclosedherein may exist as tautomers and both tautomeric forms are intended tobe encompassed by the scope of the invention, even though only onetautomeric structure is depicted.

The compounds may exist in different isomeric forms, all of which areencompassed by the present invention.

When any variable (e.g. R¹ and R², etc.) occurs more than one time inany constituent, its definition on each occurrence is independent atevery other occurrence. Also, combinations of substituents and variablesare permissible only if such combinations result in stable compounds.Lines drawn into the ring systems from substituents represent that theindicated bond may be attached to any of the substitutable ring atoms.If the ring system is polycyclic, it is intended that the bond beattached to any of the suitable carbon atoms on the proximal ring only.

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups may be on the samecarbon or on different carbons, so long as a stable structure results.The phrase “optionally substituted” should be taken to be equivalent tothe phrase “unsubstituted or substituted with one or more substituents”and in such cases the preferred embodiment will have from zero to threesubstituents. More particularly, there are zero to two substituents. Asubstituent on a saturated, partially saturated or unsaturatedheterocycle can be attached at any substitutable position.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, “C₁-C₆ alkyl” is definedto include groups having 1, 2, 3, 4, 5 or 6 carbons in a linear orbranched arrangement. For example, “C₁-C₆ alkyl” specifically includesmethyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl,hexyl, and so on. The preferred alkyl group is methyl. The term“cycloalkyl” means a monocyclic, bicyclic or polycyclic saturatedaliphatic hydrocarbon group having the specified number of carbon atoms.For example, “C₇₋₁₀cycloalkyl” includes cyclopropyl, methyl-cyclopropyl,2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and so on. Inan embodiment of the invention the term “cycloalkyl” includes the groupsdescribed immediately above and further includes monocyclic unsaturatedaliphatic hydrocarbon groups. For example, “cycloalkyl” as defined inthis embodiment includes cyclopropyl, methyl-cyclopropyl,2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, cyclopentenyl,cyclobutenyl, 7,7-dimethylbicyclo[2.2.1]heptyl and so on. Preferredcycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

“Alkoxy” represents an alkyl group of indicated number of carbon atomsattached through an oxygen bridge. “Alkoxy” therefore encompasses thedefinitions of alkyl above. Examples of suitable alkoxy groups includemethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.The preferred alkoxy group is methoxy.

The terms “haloC₁₋₆alkyl” and “haloC₁₋₆alkoxy” mean a C₁₋₆alkyl orC₁₋₆alkoxy group in which one or more (in particular, 1 to 3) hydrogenatoms have been replaced by halogen atoms, especially fluorine orchlorine atoms. Preferred are fluoroC₁₋₆alkyl and fluoroC₁₋₆alkoxygroups, in particular fluoroC₁₋₃alkyl and fluoroC₁₋₃alkoxy groups, forexample, CF₃, CHF₂, CH₂F, CH₂CH₂F, CH₂CHF₂, CH₂CF₃, OCF₃, OCHF₂, OCH₂F,OCH₂CH₂F, OCH₂CHF₂ or OCH₂CF₃, and most especially CF₃, OCF₃ and OCHF₂.

The term “hydroxyC₁₋₆alkyl” means a C₁₋₆alkyl group in which one or more(in particular, 1 to 3) hydrogen atoms have been replaced by hydroxygroups. Preferred are CH₂OH, CH₂CHOH and CHOHCH₃.

As used herein, the term “C₂₋₆alkenyl” refers to a non-aromatichydrocarbon radical, straight or branched, containing from 2 to 6 carbonatoms and at least one carbon to carbon double bond. Preferably onecarbon to carbon double bond is present, and up to four non-aromaticcarbon-carbon double bonds may be present. Alkenyl groups includeethenyl, propenyl, butenyl and 2-methylbutenyl. The straight or branchedportion of the alkenyl group may contain double bonds and may besubstituted if a substituted alkenyl group is indicated. Preferredalkenyl groups include ethenyl and propenyl.

The term “C₂₋₆alkynyl” refers to a hydrocarbon radical straight orbranched, containing from 2 to 6 carbon atoms and at least one carbon tocarbon triple bond. Up to three carbon-carbon triple bonds may bepresent. Alkynyl groups include ethynyl, propynyl, butynyl,3-methylbutynyl and so on. The straight or branched portion of thealkynyl group may contain triple bonds and may be substituted if asubstituted alkynyl group is indicated. Preferred alkynyl groups includeethynyl and propynyl.

As used herein, “C₆₋₁₀aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of 6 to 10 atoms, wherein at least one ring isaromatic. Examples of such aryl elements include phenyl, naphthyl,tetrahydronaphthyl, indanyl, tetrahydrobenzo[7]annulene, indenyl andtetrahydroindenyl. The preferred aryl group is phenyl or naphthyl,especially phenyl.

Examples of particular heterocycles of this invention arebenzimidazolyl, benzofurandionyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl,benzoxazolonyl, benzothiazolyl, benzothiadiazolyl, benzodioxolyl,benzoxadiazolyl, benzoisoxazolyl, benzoisothiazolyl, chromenyl,chromanyl, isochromanyl, carbazolyl, carbolinyl, cinnolinyl, epoxidyl,furanyl, furazanyl, imidazolyl, indolinyl, indolyl, indolizinyl,indolinyl, isoindolinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazolinyl, isoxazolinyl, oxetanyl, purinyl, pyranyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl,pyridinyl, pyrimidinyl, triazinyl, tetrazinyl, pyrrolyl, quinazolinyl,quinolyl, quinoxalinyl, quinolizinyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl,tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl,azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidyl,pyridin-2-onyl, pyrrolidinyl, imidazolinyl, pyrazolinyl, pyrrolinyl,morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,dihydroisochromenyl, dihydroimidazolonyl, dihydrotriazolonyl,dihydrobenzodioxinyl, dihydrothiazolopyrimidinyl, methylenedioxybenzoyl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl,thiazolidinonyl, imidazolonyl, isoindolinonyl, octahydroquinolizinyl,octahydroisoindolyl, imidazopyridinyl, azabicycloheptanyl, chromenonyl,triazolopyrimidinyl, dihydrobenzoxazinyl, thiazolotriazolyl,azoniabicycloheptanyl, azoniabicyclooctanyl, phthalazinyl,naphthyridinyl, quinazolinyl, pteridinyl and N-oxides thereof. Furtherparticular heterocycles include dihydroquinazolinyl,dihydrophthalazinyl, dihydroisoindolyl, tetrahydronaphthyridinyl,tetrahydrobetacarbolinyl and N-oxides thereof. Further particularheterocycles include dibenzofuranyl, naphthyridinyl, dihydrochromenyl,dihydrobenzothiazolyl, imidazothiazolyl, tetrahydroindazolyl,tetrahydrobenzothienyl, hexahydronaphthyridinyl,tetrahydropyridonaphthyridinyl, tetrahydroimidazopyridinyl,tetrahydroimidazopyrazinyl, pyrrolopyridinyl and N-oxides thereof.Attachment of a heterocyclyl substituent can occur via a carbon atom orvia a heteroatom.

A preferred 4 membered saturated heterocycle is azetidinyl.

Preferred 5 or 6 membered saturated or partially saturated heterocyclesare pyrrolidinyl, piperidyl, piperazinyl, morpholinyl,azoniabicyclo[2.2.1]heptanyl and azoniabicyclo[2.2.2]octanyl. A furtherpreferred heterocycle is thiomorpholinyl.

Preferred 5 membered unsaturated heterocycles are thienyl, thiazolyl,pyrazolyl, isoxazolyl, imidazolyl, thiadiazolyl, oxazolyl and triazolyl.Further preferred heterocycles are tetrazolyl, furyl and oxadiazolyl.

A preferred 6 membered unsaturated heterocycle is pyridinyl.

Preferred 8-10 membered saturated, partially saturated or unsaturatedheterocycles are benzothienyl, isoquinolyl, indolyl, benzothiadiazolyl,benzoxadiazolyl, thiazolotriazolyl, dihydrobenzodioxinyl,dihydrothiazolopyrimidinyl, dihydrobenzoxazinyl and dihydrobenzofuranyl.Further preferred heterocycles are benzothiazolyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzoxazolyl,dihydroindolyl, dihydroquinazolinyl, dihydrophthalazinyl, indazolyl,benzisoxazolyl, benzotriazolyl, dihydroisoindolyl,tetrahydronaphthyridinyl and triazolopyrimidinyl. Further preferredheterocycles are quinoxalinyl, tetrahydroisoquinolinyl,dibenzo[b,d]furanyl, naphthyridinyl, dihydroquinolinyl,dihydroisochromenyl, dihydrochromenyl, tetrahydroquinolinyl,dihydrobenzothiazolyl, imidazothiazolyl, tetrahydroindazolyl,tetrahydrobenzothienyl, hexahydronaphthyridinyl,tetrahydroimidazopyridinyl, tetrahydroimidazopyrazinyl andpyrrolopyridinyl.

A preferred 13 membered partially saturated heterocycle istetrahydrobetacarbolinyl.

A preferred 14 membered partially saturated heterocycle istetrahydropyridonaphthyridinyl.

Preferred 6-13 membered partially saturated hydrocarbon groups aretetrahydronaphthyl and dihydroindenyl.

As used herein, the term ‘halogen’ refers to fluorine, chlorine, bromineand iodine, of which fluorine, chlorine and bromine are preferred.

Particular compounds within the scope of the present invention include:

-   1-methyl-3-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}carbonyl)piperidinium    bis(trifluoroacetate);-   2-((1S)-1-{[(4-methoxyphenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-[(1S)-1-({[[2-(dimethylammonio)ethyl](methyl)amino]sulfonyl}amino)-7-oxooctyl]-5-phenyl-1H-imidazol-1-ium    bis(trifluoroacetate);-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   1-methyl-4-(2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}ethyl)piperazinedium    tris(trifluoroacetate);-   1-methyl-2-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}carbonyl)piperidinium    bis(trifluoroacetate);-   1-(3-oxo-3-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}propyl)piperidinium    bis(trifluoroacetate);-   2-((1S)-1-{[(1-methylpyrrolidinium-3-yl)carbonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    bis(trifluoroacetate);-   1-methyl-4-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}carbonyl)piperidinium    bis(trifluoroacetate);-   2-{(1S)-7-oxo-1-[(2-thienylcarbonyl)amino]octyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-7-oxo-1-[(1,3-thiazol-5-ylcarbonyl)amino]octyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(4-methyl-1,2,3-thiadiazol-5-yl)carbonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-1-[(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(4-cyanophenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-1-[(2-naphthylsulfonyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-1-[(1-benzothien-3-ylsulfonyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(4-chlorophenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(3-methoxyphenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   1,2-dimethyl-4-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}sulfonyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   2-((1S)-1-{[(3,5-dimethylisoxazol-4-yl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   4-[({1-[5-(2-methoxyphenyl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   4-[({1-[5-(3-methoxyphenyl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   4-[({1-[5-(4-fluorophenyl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   4-[({1-[5-(4-chlorophenyl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   4-[({1-[5-(4-bromophenyl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   4-[({1-[5-(2-chlorophenyl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   4-[({1-[5-(3,4-dichlorophenyl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   4-[({1-[5-(4-cyanophenyl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   4-[({1-[5-(3-cyanophenyl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   4-({[1-(4,5-diphenyl-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl)-1-methylpiperidinium    bis(trifluoroacetate);-   4-({[1-(4,5-diphenyl-1,3-oxazol-2-yl)-7-oxooctyl]amino}carbonyl)-1-methylpiperidinium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    chloride;-   1-methyl-4-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}carbonyl)piperidinium    dichloride;-   1-methyl-4-[4-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}carbonyl)phenyl]piperazinedium    tris(trifluoroacetate);-   3-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}carbonyl)-1-pyridin-2-ylpiperidinium    bis(trifluoroacetate);-   3-(2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}ethyl)-6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidin-4-ium    bis(trifluoroacetate);-   2-(3-oxo-3-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}propyl)-2-azoniabicyclo[2.2.1]heptane    bis(trifluoroacetate);-   4-(2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}-1-pyridinium-3-ylethyl)morpholin-4-ium    tris(trifluoroacetate);-   1-methyl-4-({[(1S)-1-(4-methyl-5-phenyl-1H-imidazol-1-ium-2-yl)-7-oxooctyl]amino}carbonyl)piperidinium    bis(trifluoroacetate);-   4-({[(1S)-1-(5-biphenyl-4-yl-1H-imidazol-1-ium-2-yl)-7-oxooctyl]amino}carbonyl)-1-methylpiperidinium    bis(trifluoroacetate);-   1-methyl-4-[({(1S)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]piperidinium    bis(trifluoroacetate);-   4-[({(1S)-1-[5-(3-chlorophenyl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   4-{[((1S)-1-{5-[3,5-bis(trifluoromethyl)phenyl]-1H-imidazol-1-ium-2-yl}-7-oxooctyl)amino]carbonyl}-1-methylpiperidinium    bis(trifluoroacetate);-   1-methyl-4-{[((1S)-7-oxo-1-{5-[3-(trifluoromethyl)phenyl]-1H-imidazol-1-ium-2-yl}octyl)amino]carbonyl}piperidinium    bis(trifluoroacetate);-   2-((1S)-1-{[(3-cyanophenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-7-oxo-1-[(phenylsulfonyl)amino]octyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   4-methyl-7-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}sulfonyl)-3,4-dihydro-2H-1,4-benzoxazin-4-ium    bis(trifluoroacetate);-   2-[(1S)-1-({[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]sulfonyl}amino)-7-oxooctyl]-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(5-chloro-2-thienyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   1,3,5-trimethyl-4-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}sulfonyl)-1H-pyrazol-1-ium    bis(trifluoroacetate);-   2-[(1S)-1-({[5-(2-methyl-1,3-thiazol-4-yl)-2-thienyl]sulfonyl}amino)-7-oxooctyl]-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-1-[({5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl}sulfonyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(5-isoxazol-3-yl-2-thienyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   1-methyl-4-{[((1S)-7-oxo-1-{5-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-ium-2-yl}octyl)amino]carbonyl}piperidinium    bis(trifluoroacetate);-   4-{[((1S)-1-{5-[4-(difluoromethoxy)phenyl]-1H-imidazol-1-ium-2-yl}-7-oxooctyl)amino]carbonyl}-1-methylpiperidinium    bis(trifluoroacetate);-   4-[({(1S)-1-[5-(3,4-difluorophenyl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   2-((1S)-1-{[(2-nitrophenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(3-nitrophenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-[(1S)-1-({[4-(acetylamino)phenyl]sulfonyl}amino)-7-oxooctyl]-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(2-cyanophenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(2-chloro-4-cyanophenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(3-fluoro-4-nitrophenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-[(1S)-1-({[2-(methoxycarbonyl)-3-thienyl]sulfonyl}amino)-7-oxooctyl]-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(2,5-dimethoxyphenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(3-fluorophenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(3-cyano-4-fluorophenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-[(1S)-1-({[4-(difluoromethoxy)phenyl]sulfonyl}amino)-7-oxooctyl]-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-[(1S)-1-({[3-(difluoromethoxy)phenyl]sulfonyl}amino)-7-oxooctyl]-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-1-[(2,1,3-benzothiadiazol-5-ylsulfonyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-1-[(2,3-dihydro-1-benzofuran-5-ylsulfonyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-morpholin-4-yl-5-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}sulfonyl)pyridinium    bis(trifluoroacetate);-   2-{(1S)-1-[(2,1,3-benzoxadiazol-4-ylsulfonyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(4-fluorophenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(4-nitrophenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(2-fluorophenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(3,4-dimethoxyphenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(3,4-difluorophenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   5-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}sulfonyl)isoquinolinium    bis(trifluoroacetate);-   2-((1S)-1-{[(4-carboxyphenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   1-methyl-4-[({(1S)-7-oxo-1-[5-(3-thienyl)-1H-imidazol-3-ium-2-yl]octyl}amino)carbonyl]piperidinium    bis(trifluoroacetate);-   2-[2-((1S)-1-{[(1-methylpiperidinium-4-yl)carbonyl]amino}-7-oxooctyl)-1H-imidazol-3-ium-5-yl]pyridinium    tris(trifluoroacetate);-   4-[({(1S)-1-[5-(5-chloro-3-methyl-1-benzothien-2-yl)-1H-imidazol-3-ium-2-yl]-7-oxooctyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   1-methyl-4-[({(1S)-7-oxo-1-[5-(3-phenylisoxazol-5-yl)-1H-imidazol-3-ium-2-yl]octyl}amino)carbonyl]piperidinium    bis(trifluoroacetate);-   1-methyl-4-{[((1S)-1-{5-[6-methyl-2-(trifluoromethyl)[1,3]thiazolo[3,2-b][1,2,4]triazol-5-yl]-1H-imidazol-3-ium-2-yl}-7-oxooctyl)amino]carbonyl}piperidinium    bis(trifluoroacetate);-   1-methyl-4-[({(1S)-1-[1-methyl-4-(2-naphthyl)-1H-imidazol-3-ium-2-yl]-7-oxooctyl}amino)carbonyl]piperidinium    bis(trifluoroacetate);-   2-(5-methoxy-2-methyl-1H-indol-3-yl)-N-{(1S)-1-[5-(2-naphthyl)-4H-1,2,4-triazol-3-yl]-7-oxononyl}acetamide;-   2-(5-methoxy-2-methyl-1H-indol-3-yl)-N-[7-oxo-1-(4-phenyl-2-thienyl)nonyl]acetamide;-   4-[({(1S)-1-[5-(1-benzothien-3-yl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   2-{(1S)-1-[(3,4-difluorobenzoyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[4-(acetylamino)benzoyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[4-(aminosulfonyl)benzoyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   4-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}carbonyl)pyridinium    bis(trifluoroacetate);-   3-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}carbonyl)pyridinium    bis(trifluoroacetate);-   2-((1S)-1-{[(3,5-dimethylisoxazol-4-yl)carbonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-1-[(2,3-dihydro-1,4-benzodioxin-6-ylcarbonyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-1-[(3-nitrobenzoyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-1-[(3-cyanobenzoyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-1-[(4-cyanobenzoyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   1-methyl-4-({[7-oxo-1-(4-phenyl-2-thienyl)nonyl]amino}carbonyl)piperidinium    trifluoroacetate;-   4-[({(1S)-6-carboxy-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]hexyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   2-((1S)-6-carboxy-1-{[(3-nitrophenyl)sulfonyl]amino}hexyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   4-[({(1S)-6-carboxy-1-[5-(3-methoxyphenyl)-1H-imidazol-1-ium-2-yl]hexyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   2-((1S)-6-carboxy-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}hexyl)-5-(3-methoxyphenyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-6-carboxy-1-{[(3-nitrophenyl)sulfonyl]amino}hexyl)-5-(3-methoxyphenyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-6-carboxy-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}hexyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-7-(Hydroxyamino)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-{((1S)-1-[(3-fluoro-4-nitrobenzoyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-cyano-5-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}carbonyl)pyridinium    bis(trifluoroacetate);-   2-((1S)-1-{[(4-cyanophenyl)sulfonyl]amino}-7-oxooctyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-(2-naphthyl)-2-((1S)-1-{[(3-nitrophenyl)sulfonyl]amino}-7-oxooctyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-[(1S)-1-({[[2-(dimethylammonio)ethyl](methyl)amino]sulfonyl}amino)-7-oxooctyl]-5-(2-naphthyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   5-(2-naphthyl)-2-{(1S)-7-oxo-1-[(1,3-thiazol-5-ylcarbonyl)amino]octyl}-1H-imidazol-1-ium    trifluoroacetate;-   5-(3-chlorophenyl)-2-((1S)-1-{[(4-cyanophenyl)sulfonyl]amino}-7-oxooctyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-(3-chlorophenyl)-2-((S)-1-{[(3-nitrophenyl)sulfonyl]amino}-7-oxooctyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(4-cyanophenyl)sulfonyl]amino}-7-oxooctyl)-5-(3-methoxyphenyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-(3-methoxyphenyl)-2-((1S)-1-{[(3-nitrophenyl)sulfonyl]amino}-7-oxooctyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-(3-methoxyphenyl)-2-{(1S)-7-oxo-1-[(1,3-thiazol-5-ylcarbonyl)amino]octyl}-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-7-[(2-aminophenyl)amino]-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-(3-methoxyphenyl)-2-[(1S)-1-({[(3S)-1-methylpyrrolidinium-3-yl]carbonyl}amino)-7-oxooctyl]-1H-imidazol-1-ium    bis(trifluoroacetate);-   (3S)-3-[({(1S)-1-[5-(3-methoxyphenyl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   (3S)-1-isopropyl-3-[({(1S)-1-[5-(3-methoxyphenyl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]piperidinium    bis(trifluoroacetate);-   5-(3-chlorophenyl)-2-[(1S)-1-({[(3R)-1-methylpyrrolidinium-3-yl]carbonyl}amino)-7-oxooctyl]-1H-imidazol-1-ium    bis(trifluoroacetate);-   2-[(1S)-1-({[(3R)-1-methylpyrrolidinium-3-yl]carbonyl}amino)-7-oxooctyl]-5-(2-naphthyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   4-methyl-2-[({(1S)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]morpholin-4-ium    bis(trifluoroacetate);-   4-[({(1S)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]-1-azoniabicyclo[2.2.2]octane    bis(trifluoroacetate);-   4-[2-({(1S)-1-[5-(3-chlorophenyl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)-1-methyl-2-oxoethyl]morpholin-4-ium    bis(trifluoroacetate);-   2-[(1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-(methylamino)-7-oxoheptyl]-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-(3-methoxyphenyl)-2-[(1S)-1-({[(3R)-1-methylpyrrolidinium-3-yl]carbonyl}amino)-7-oxooctyl]-1H-imidazol-1-ium    bis(trifluoroacetate);-   (3R)-3-[({(1S)-1-[5-(3-methoxyphenyl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   5-(3-chlorophenyl)-2-[(1S)-1-({[(3S)-1-methylpyrrolidinium-3-yl]carbonyl}amino)-7-oxooctyl]-1H-imidazol-ium    bis(trifluoroacetate);-   2-[(1S)-1-({[(3S)-1-methylpyrrolidinium-3-yl]carbonyl}amino)-7-oxooctyl]-5-(2-naphthyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   1-methyl-4-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)nonyl]amino}carbonyl)piperidinium    bis(trifluoroacetate);    and the pharmaceutically acceptable free bases, salts, alternative    salts and stereoisomers thereof.

Further particular compounds within the scope of the present inventionare:

-   2-(5-methoxy-2-methyl-1H-indol-3-yl)-N-{(1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}acetamide;-   2-(5-methoxy-2-methyl-1H-indol-3-yl)-N-{(1S)-1-[5-(2-naphthyl)-1,3-oxazol-2-yl]-7-oxononyl}acetamide;-   5-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-2-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-(5-methoxy-2-methyl-1H-indol-3-yl)-N-[7-oxo-1-(2-phenyl-1,3-thiazol-5-yl)nonyl]acetamide;-   2-((1S)-1-{[(1-methylpiperidinium-4-yl)carbonyl]amino}-7-oxononyl)-4-phenylpyridinium    bis(trifluoroacetate);-   (7S)-7-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]heptanoic    acid;-   (7S)-7-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]heptanamide;-   (7S)-7-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-[5-(2-naphthyl)-4H-1,2,4-triazol-3-yl]heptanoic    acid;-   (7S)-7-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-[5-(2-naphthyl)-4H-1,2,4-triazol-3-yl]heptanamide;-   2-(5-methoxy-2-methyl-1H-indol-3-yl)-N-{(1S)-1-[5-(2-naphthyl)-1,2,4-oxadiazol-3-yl]-7-oxononyl}acetamide;-   2-(5-methoxy-2-methyl-1H-indol-3-yl)-N-{(1S)-1-[3-(2-naphthyl)-1,2,4-oxadiazol-5-yl]-7-oxononyl}acetamide;-   2-{(1S)-1-[(methoxycarbonyl)amino]-7-oxononyl}-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(dimethylamino)carbonyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   3-nitro-N-[7-oxo-1-(4-phenyl-2-furyl)octyl]benzenesulfonamide;-   2-((1S)-7-[(ethylsulfonyl)amino]-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-(2-naphthyl)-2-((1S)-8,8,8-trifluoro-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-1H-imidazol-1-ium    trifluoroacetate;-   3-nitro-N-[7-oxo-1-(4-phenyl-1,3-thiazol-2-yl)octyl]benzenesulfonamide;-   2-((1S)-7-amino-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-7-(dimethylamino)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-7-(isopropylamino)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-7-anilino-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-7-(benzylamino)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-[(methylsulfonyl)amino]-7-oxoheptyl}-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   1-methyl-4-[({(1S)-1-[5-(2-naphthyl)-4h-1,2,4-triazol-3-yl]-7-oxononyl}amino)carbonyl]piperidinium    trifluoroacetate;-   (3S)-1-methyl-3-[({(1S)-1-[5-(2-naphthyl)-4H-1,2,4-triazol-3-yl]-7-oxononyl}amino)carbonyl]pyrrolidinium    trifluoroacetate;-   (3S)-1-methyl-3-[({(1S)-1-[5-(2-naphthyl)-4H-1,2,4-triazol-3-yl]-7-oxononyl}amino)carbonyl]piperidinium    trifluoroacetate;-   N-{(1S)-1-[5-(2-naphthyl)-4H-1,2,4-triazol-3-yl]-7-oxononyl}-1,3-thiazole-5-carboxamide;-   4-cyano-N-{(1S)-1-[3-(2-naphthyl)-1H-1,2,4-triazol-5-yl]-7-oxononyl}benzenesulfonamide;-   2-((1S)-7-[methoxy(methyl)amino]-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   1-methyl-4-[({(1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxoheptyl}amino)carbonyl]piperidinium    bis(trifluoroacetate);-   4-[({(1S)-7-(hydroxyamino)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxoheptyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   2-{(1S)-6-carboxy-1-[(1,3-thiazol-5-ylcarbonyl)amino]hexyl}-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   4-[({(1S)-7-[(2-aminophenyl)amino]-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxoheptyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   2-[(1S)-6-carboxy-1-({[(3R)-1-methylpyrrolidinium-3-yl]carbonyl}amino)hexyl]-5-(2-naphthyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   2-[(1S)-6-carboxy-1-({[(3S)-1-methylpyrrolidinium-3-yl]carbonyl}amino)hexyl]-5-(2-naphthyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   2-((1S)-6-carboxy-1-{[(dimethylamino)sulfonyl]amino}hexyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   4-[({(1S)-7-[methoxy(methyl)amino]-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxoheptyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxo-7-{[(trifluoromethyl)sulfonyl]amino}heptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-7-(ethylamino)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   (3S)-3-[({(1S)-1-[3-(3,5-dichlorophenyl)-1H-1,2,4-triazol-5-yl]-7-oxononyl}amino)carbonyl]-1-methylpyrrolidinium    trifluoroacetate;-   4-[({((1S)-1-[3-(3,5-dichlorophenyl)-1H-1,2,4-triazol-5-yl]-7-oxononyl}amino)carbonyl]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate;-   N-{(1S)-1-[3-(3,5-dichlorophenyl)-1H-1,2,4-triazol-5-yl]-7-oxononyl}-2-(5-methoxy-2-methyl-1H-indol-3-yl)acetamide;-   2-(5-methoxy-2-methyl-1H-indol-3-yl)-N-{(1S)-1-[3-(3-methoxyphenyl)-1H-1,2,4-triazol-5-yl]-7-oxononyl}acetamide;-   2-(5-methoxy-2-methyl-1H-indol-3-yl)-N-[7-oxo-1-(4-phenyl-1,3-thiazol-2-yl)octyl]acetamide;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-{(1S)-1-[(1H-indol-3-ylacetyl)amino]-7-oxononyl}-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-bromo-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-fluoro-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   1-[2-({(1S)-1-[5-(2-naphthyl)-1H-imidazol-3-ium-2-yl]-7-oxononyl}amino)-2-oxoethyl]-1H-benzimidazol-3-ium    bis(trifluoroacetate);-   2-((1S)-1-{[(7-methoxy-1-benzofuran-2-yl)carbonyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-{[(5-methoxy-1H-indol-2-yl)carbonyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-fluoro-1H-indol-2-yl)carbonyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   6-[2-({(1S)-1-[5-(2-naphthyl)-1H-imidazol-3-ium-2-yl]-7-oxononyl}amino)-2-oxoethyl][1,2,4]triazolo[1,5-a]pyrimidin-4-ium    bis(trifluoroacetate);-   5-(2-naphthyl)-2-((1S)-7-oxo-1-{[(4-phenyl-1,3-thiazol-2-yl)acetyl]amino}nonyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-chloro-1-benzothien-3-yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(4-chloro-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   5-(2-naphthyl)-2-((1S)-7-oxo-1-{[(2-oxo-1,3-benzoxazol-3(2H)-yl)acetyl]amino}nonyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(6-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-ethyl-1-[3-({(1S)-1-[5-(2-naphthyl)-1H-imidazol-3-ium-2-yl]-7-oxononyl}amino)-3-oxopropyl]-1H-benzimidazol-3-ium    bis(trifluoroacetate);-   5-(2-naphthyl)-2-{(1S)-1-[(1-naphthylacetyl)amino]-7-oxononyl}-1H-imidazol-3-ium    trifluoroacetate;-   5-(2-naphthyl)-2-{(1S)-1-[(2-naphthylacetyl)amino]-7-oxononyl}-1H-imidazol-3-ium    trifluoroacetate;-   5-(2-naphthyl)-2-((1S)-7-oxo-1-{[(2-oxoquinazolin-1(2H)-yl)acetyl]amino}nonyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(4-methyl-1-oxophthalazin-2(1H)-yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   5-(2-naphthyl)-2-{(1S)-7-oxo-1-[(phenylacetyl)amino]nonyl}-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(2,6-dichlorophenyl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(2,4-dichlorophenyl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-[(1S)-1-({[2-fluoro-6-(trifluoromethyl)phenyl]acetyl}amino)-7-oxononyl]-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-[(1S)-1-({[2-fluoro-3-(trifluoromethyl)phenyl]acetyl}amino)-7-oxononyl]-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-[(1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxo-7-(1,3-thiazol-2-ylamino)heptyl]-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-[(1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxo-7-(1,3,4-thiadiazol-2-ylamino)heptyl]-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-methyl-1-[2-({(1S)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxononyl}amino)-2-oxoethyl]-1H-benzimidazol-3-ium    bis(trifluoroacetate);-   1-[2-({(1S)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxononyl}amino)-2-oxoethyl]-2-(trifluoromethyl)-1H-benzimidazol-3-ium    bis(trifluoroacetate);-   2-{(1S)-1-[(1H-indazol-1-ylacetyl)amino]-7-oxononyl}-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   3-[2-({(1S)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxononyl}amino)-2-oxoethyl]quinolinium    bis(trifluoroacetate);-   2-((1S)-1-{[(dimethylamino)(oxo)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-1-[(1,2-benzisoxazol-3-ylacetyl)amino]-7-oxononyl}-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(2-methyl-1H-indol-1-yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-1-[(1H-1,2,3-benzotriazol-1-ylacetyl)amino]-7-oxononyl}-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(5-cyano-1H-indol-1-yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(dimethylammonio)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   1-methyl-4-[({(1S)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxononyl}amino)carbonyl]piperidinium    bis(trifluoroacetate);-   4-[({(1S)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxononyl}amino)carbonyl]-1-azoniabicyclo[2.2.2]octane    bis(trifluoroacetate);-   (7S)-7-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-N-methyl-7-[5-(2-naphthyl)-4H-1,2,4-triazol-3-yl]heptanamide;-   4-[({(1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}amino)carbonyl]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate;-   2-ethyl-1-[3-({(1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}amino)-3-oxopropyl]-1H-benzimidazol-3-ium    trifluoroacetate;-   6-[2-({(1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}amino)-2-oxoethyl][1,2,4]triazolo[1,5-a]pyrimidin-3-ium    trifluoroacetate;-   1-methyl-4-[({(1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}amino)carbonyl]piperidinium    trifluoroacetate;-   (3R)-1-methyl-3-[({(1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}amino)carbonyl]pyrrolidinium    trifluoroacetate;-   (4R)-4-[({(1S)-1-[5-(2-naphthyl)-1H-imidazol-3-ium-2-yl]-7-oxononyl}amino)carbonyl]-2,3,4,9-tetrahydro-1H-beta-carbolin-2-ium    bis(trifluoroacetate);-   (7S)-7-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-N-methyl-7-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]heptanamide;-   4-[({(1S)-6-carboxy-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]hexyl}amino)carbonyl]-1-methylpiperidinium    trifluoroacetate;-   (7S)-7-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]-7-[(1,3-thiazol-4-ylcarbonyl)amino]heptanoic    acid;-   4-[({(1S)-1-[5-(2,3-dihydro-1,4-benzodioxin-6-yl)-1H-imidazol-3-ium-2-yl]-7-oxononyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   2-(5-methoxy-2-methyl-1H-indol-3-yl)-N-{(1S)-1-[4-(2-naphthyl)-1,3-oxazol-2-yl]-7-oxononyl}acetamide;-   2-((1S)-7-(methylamino)-7-oxo-1-{[(1-pyridin-2-ylpiperidin-3-yl)carbonyl]amino}heptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-[2-({(1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxoheptyl}amino)-2-oxoethyl]-2,3-dihydro-1H-isoindolium    bis(trifluoroacetate);-   2-{(1S)-7-(methylamino)-7-oxo-1-[(piperidin-1-ylacetyl)amino]heptyl}-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   4-[({(1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxoheptyl}amino)carbonyl]-1-azoniabicyclo[2.2.2]octane    bis(trifluoroacetate);-   5-[({(1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxoheptyl}amino)carbonyl]-1,2,3,4-tetrahydro-1,8-naphthyridin-1-ium    bis(trifluoroacetate);-   2-((1S)-7-(methylamino)-7-oxo-1-{[(5-pyrrolidin-1-yl-2H-tetrazol-2-yl)acetyl]amino}heptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-7-(methylamino)-7-oxo-1-[(1,3-thiazol-5-ylcarbonyl)amino]heptyl}-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-7-(methylamino)-1-{[(4-methyl-1,2,3-thiadiazol-5-yl)carbonyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-7-(methylamino)-7-oxo-1-[(pyridin-3-ylcarbonyl)amino]heptyl}-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-7-(methylamino)-7-oxo-1-[(phenylacetyl)amino]heptyl}-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   (7S)-7-({[(3S)-1-methylpyrrolidin-3-yl]carbonyl}amino)-7-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]heptanoic    acid;-   (3S)-3-[({(1S)-6-carboxy-1-[5-(2-naphthyl)-4H-1,2,4-triazol-3-yl]hexyl}amino)carbonyl]-1-methylpyrrolidinium    trifluoroacetate;-   (3S)-3-[({(1S)-7-amino-1-[5-(2-naphthyl)-4H-1,2,4-triazol-3-yl]-7-oxoheptyl}amino)carbonyl]-1-methylpyrrolidinium    trifluoroacetate;-   4-[({(1S)-1-[5-(2,3-dihydro-1,4-benzodioxin-5-yl)-1H-imidazol-3-ium-2-yl]-7-oxononyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   4-[({(1S)-1-[5-(1,3-benzothiazol-2-yl)-1H-imidazol-3-ium-2-yl]-7-oxononyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   4-[({(1S)-1-[5-(1-benzothien-2-yl)-1H-imidazol-3-ium-2-yl]-7-oxononyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   2-[(1S)-1-{[(benzylamino)carbonyl]amino}-7-(methylamino)-7-oxoheptyl]-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-[(1S)-1-({[(4-methoxyphenyl)amino]carbonyl}amino)-7-(methylamino)-7-oxoheptyl]-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-[(1S)-1-{[(cyclopentylamino)carbonyl]amino}-7-(methylamino)-7-oxoheptyl]-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-7-(methylamino)-1-{[(3-nitrophenyl)sulfonyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-[(1S)-1-{[(4-cyanophenyl)sulfonyl]amino}-7-(methylamino)-7-oxoheptyl]-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-[(1S)-7-(methylamino)-1-({[(3S)-1-methylpyrrolidinium-3-yl]carbonyl}amino)-7-oxoheptyl]-5-(2-naphthyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   2-[(1S)-7-(methylamino)-1-({[(3R)-1-methylpyrrolidinium-3-yl]carbonyl}amino)-7-oxoheptyl]-5-(2-naphthyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   2-[(1S)-1-{[(benzyloxy)carbonyl]amino}-7-(methylamino)-7-oxoheptyl]-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   1-methyl-4-[({(1R)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxononyl}amino)carbonyl]piperidinium    bis(trifluoroacetate);-   (3R)-3-[({(1S)-6-carboxy-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]hexyl}amino)carbonyl]-1-methylpyrrolidinium    trifluoroacetate;-   5-methoxy-N-{(1S)-7-(methylamino)-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]-7-oxoheptyl}-1H-indole-2-carboxamide;-   (7S)-7-{[(benzylamino)carbonyl]amino}-N-methyl-7-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]heptanamide;-   2-((1R)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   4-[({((S)-1-[5-(4-methoxyquinolin-2-yl)-1H-imidazol-3-ium-2-yl]-7-oxononyl}amino)carbonyl]-1-methylpiperidinium    bis(trifluoroacetate);-   3-[2-((1S)-1-{[(1-methylpiperidinium-4-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]quinolinium    tris(trifluoroacetate);-   6-[2-((1S)-1-{[(1-methylpiperidinium-4-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]quinolinium    tris(trifluoroacetate);-   1-methyl-4-({[(1S)-7-oxo-1-(5-quinolin-2-yl-1H-imidazol-1-ium-2-yl)nonyl]amino}carbonyl)piperidinium    bis(trifluoroacetate);-   4-({[(1S)-1-(5-isoquinolin-3-yl-1H-imidazol-1-ium-2-yl)-7-oxononyl]amino}carbonyl)-1-methylpiperidinium    bis(trifluoroacetate);-   1-methyl-N-{1-[2-(2-naphthyl)-1H-imidazol-5-yl]-7-oxononyl}piperidine-4-carboxamide;-   1-methyl-N-[7-oxo-1-(3-phenyl-1H-pyrazol-5-yl)nonyl]piperidine-4-carboxamide;-   2-[(1S)-1-(acetylamino)-7-oxononyl]-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(1,3-dimethylpyrrolidinium-3-yl)carbonyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   4-[3-({(1S)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxononyl}amino)-3-oxopropyl]thiomorpholin-4-ium    1,1-dioxide bis(trifluoroacetate);-   5-(2-naphthyl)-2-{(1S)-7-oxo-1-[(trifluoroacetyl)amino]nonyl}-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[2-(dimethylammonio)-2-methylpropanoyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   2-[(1S)-1-{[3-(2-ethyl-1H-benzimidazol-1-yl)propanoyl]amino}-7-(methylamino)-7-oxoheptyl]-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   6-[2-({(1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxoheptyl}amino)-2-oxoethyl][1,2,4]triazolo[1,5-a]pyrimidin-3-ium    bis(trifluoroacetate);-   2-((1S)-7-(methylamino)-7-oxo-1-{[(2-oxoquinazolin-1(2H)-yl)acetyl]amino}heptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-7-(methylamino)-7-oxo-1-{[(2-oxo-1,3-benzoxazol-3(2H)-yl)acetyl]amino}heptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   1-ethyl-3-[({(1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxoheptyl}amino)carbonyl]piperidinium    bis(trifluoroacetate);-   2-((1S)-1-{[methoxy(oxo)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[2-methyl-2-(methylammonio)propanoyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   2-(5-methoxy-2-methyl-1H-indol-3-yl)-N-[7-oxo-1-(3-phenyl-1H-pyrazol-5-yl)nonyl]acetamide;-   1-methyl-4-({[(1S)-7-oxo-1-(5-quinolin-2-yl-1H-imidazol-1-ium-2-yl)nonyl]amino}carbonyl)piperidinium    dichloride;-   1-methyl-4-[({(1S)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxononyl}amino)(oxo)acetyl]piperazin-1-ium    bis(trifluoroacetate);-   2-((1S)-1-{[morpholin-4-yl(oxo)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[amino(oxo)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[3-(diethylammonio)propanoyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   2-((1S)-1-{[3-(dimethylammonio)propanoyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   2-((1S)-1-{[(5-cyano-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-1-[(carboxycarbonyl)amino]-7-oxononyl}-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-1-[(methylsulfonyl)amino]-7-oxononyl}-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(dimethylamino)sulfonyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-methoxy-2-methyl-3-(2-oxo-2-{[(1S)-7-oxo-1-(4-phenylpyridinium-2-yl)nonyl]amino}ethyl)-1H-indolium    bis(trifluoroacetate);-   2-ethyl-1-(3-oxo-3-{[(1S)-7-oxo-1-(4-phenylpyridinium-2-yl)nonyl]amino}propyl)-1H-3,1-benzimidazol-1-ium    bis(trifluoroacetate);-   1-methyl-N-{(1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}piperidine-4-carboxamide;-   6-[2-((1S)-1-{[(1-methylpiperidinium-4-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]quinolinium    trichloride;-   N-{(1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}quinuclidine-4-carboxamide;-   4-methoxy-2-[2-((1S)-1-{[(1-methylpiperidinium-4-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-3-ium-5-yl]quinolinium    trichloride;    and the pharmaceutically acceptable free bases, salts, alternative    salts and stereoisomers thereof.

Particular intermediates within the scope of the present inventioninclude:

-   2-[(1S)-1-Ammonio-6-carboxyhexyl]-5-(2-naphthyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   (1S)-1-[3-(2-Naphthyl)-1H-1,2,4-triazol-5-yl]-7-oxononan-1-aminium    trifluoroacetate;-   tert-Butyl    {(1S)-1-[5-(2-naphthyl)-1H-imidazol-2-yl]-7-oxononyl}carbamate;-   (1S)-7-oxo-1-(4-phenylpyridin-2-yl)nonan-1-aminium trifluoroacetate;-   2-[(1S)-1-Ammonio-7-oxooctyl]-5-(2-naphthyl)-1H-imidazol-3-ium    bis(trifluoroacetate);-   2-[(1S)-1-Ammonio-7-oxooctyl]-5-phenyl-1H-imidazol-3-ium    bis(trifluoroacetate);    and the pharmaceutically acceptable bases, salts, alternative salts    and stereoisomers thereof.

Further particular compounds within the scope of the present inventionsare:

-   2-{(1S)-1-[(carboxycarbonyl)amino]-7-oxononyl}-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[morpholin-4-yl(oxo)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-(2-naphthyl)-2-{(1S)-7-oxo-1-[(trifluoroacetyl)amino]nonyl}-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-ium    dichloride;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-[4-(1H-pyrazol-1-yl)phenyl]-1H-imidazol-3-ium    trifluoroacetate;-   5-(2-methoxyquinolin-3-yl)-2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-3-ium    bis(trifluoroacetate);-   2-((1S)-1-{[3-(dimethylammonio)propanoyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-ium    dichloride;-   4-methoxy-2-[2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]quinolinium    trichloride;-   N-{(1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]-5-oxoheptyl}quinuclidine-4-carboxamide;-   N-{(1S)-1-[5-(4-methoxyquinolin-2-yl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}-1-methylazetidine-3-carboxamide;-   5-(hydroxymethyl)-2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    trifluoroacetate;-   4-{[2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]methyl}morpholin-4-ium    bis(trifluoroacetate);-   2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-1H-imidazol-1-ium    trifluoroacetate;-   5-(2-carboxyethyl)-2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-acetyl-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-cyclohexyl-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoundecyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-7-cyclopropyl-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-9-methyl-7-oxodecyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-8-hydroxy-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-7-(2-furyl)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-[(1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-8-(methylsulfinyl)-7-oxooctyl]-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-[(1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-8-(methylsulfonyl)-7-oxooctyl]-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-8-(aminosulfonyl)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   1-methyl-4-({[(1S)-7-oxo-1-(4-phenyl-1H-imidazol-3-ium-2-yl)-7-pyridin-2-ylheptyl]amino}carbonyl)piperidinium    bis(trifluoroacetate);-   2-((1S)-7-amino-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-6-carboxy-1-{[(dimethylamino)sulfonyl]amino}hexyl)-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-7-(methylamino)-7-oxo-1-{[(1-pyridin-2-ylpiperidin-3-yl)carbonyl]amino}heptyl)-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-[(1S)-1-{[(benzylamino)carbonyl]amino}-7-(methylamino)-7-oxoheptyl]-5-(2-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   5-(2-methoxyquinolin-3-yl)-2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-3-ium-L-tartrate;-   2-((1S)-1-{[(1-methyl-1H-indol-3-yl)carbonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-1H-indol-2-yl)carbonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(6-fluoro-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-{(1S)-1-[(1H-indol-3-ylacetyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-{(1S)-1-[(1H-indol-3-ylcarbonyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-bromo-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(7-methoxy-6,7-dihydro-1-benzofuran-2-yl)carbonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-{(1S)-1-[(1-naphthylacetyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-fluoro-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-chloro-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-{(1S)-1-[(1H-indol-2-ylcarbonyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-fluoro-1H-indol-2-yl)carbonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-hydroxy-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(6-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   6-(2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-3-ium-2-yl)octyl]amino}ethyl)[1,2,4]triazolo[1,5-a]pyrimidin-3-ium    bis(trifluoroacetate);-   3-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-3-ium-2-yl)octyl]amino}carbonyl)-3,4-dihydrospiro[isochromene-1,4′-piperidinium]bis(trifluoroacetate);-   4-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-3-ium-2-yl)octyl]amino}carbonyl)-3,4-dihydrospiro[chromene-2,4′-piperidinium]bis(trifluoroacetate);-   5-chloro-2-(2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-3-ium-2-yl)octyl]amino}ethyl)-1H-3,1-benzimidazol-3-ium    bis(trifluoroacetate);-   2-((1S)-7-oxo-1-{[(2-oxoquinazolin-1(2H)-yl)acetyl]amino}octyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-7-oxo-1-{[(2-oxo-1,3-benzoxazol-3(2H)-yl)acetyl]amino}octyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-{(1S)-1-[(2H-indazol-2-ylacetyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   3-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-3-ium-2-yl)octyl]amino}carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidinium]bis(trifluoroacetate);-   2-((1S)-7-oxo-1-{[(2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)carbonyl]amino}octyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-cyano-1H-indol-1-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-{(1S)-1-[(2-naphthylacetyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-chloro-1-benzothien-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-chloro-1H-indazol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium    trifluoroacetate;-   2-(2-{(1S)-1-[(1-azoniabicyclo[2.2.2]oct-4-ylcarbonyl)amino]-7-oxononyl}-1H-imidazol-1-ium-5-yl)-4-methoxyquinolinium    tris(trifluoroacetate);-   4-methoxy-2-[2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]quinolinium    bis(trifluoroacetate);-   5-methoxy-N-{(1S)-1-[5-(2-naphthyl)-1,3-oxazol-2-yl]-7-oxononyl}-1H-indole-2-carboxamide;-   1-methyl-4-[({(1S)-1-[5-(2-naphthyl)-1,3-oxazol-2-yl]-7-oxononyl}amino)carbonyl]piperidinium    trifluoroacetate;-   4-[({(1S)-1-[5-(2-naphthyl)-1,3-oxazol-2-yl]-7-oxononyl}amino)carbonyl]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate;-   N,N,2-trimethyl-1-({(1S)-1-[5-(2-naphthyl)-1,3-oxazol-2-yl]-7-oxononyl}amino)-1-oxopropan-2-aminium    trifluoroacetate;-   1-methyl-3-[({(1S)-1-[5-(2-naphthyl)-1,3-oxazol-2-yl]-7-oxononyl}amino)carbonyl]azetidinium    trifluoroacetate;-   N-{(1S)-1-[5-(2-naphthyl)-1,3-oxazol-2-yl]-7-oxononyl}acetamide;-   N,N-dimethyl-N′-{(1S)-1-[5-(2-naphthyl)-1,3-oxazol-2-yl]-7-oxononyl}ethanediamide;-   8-[2-(1-{[(1-methylpiperidinium-4-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]quinolinium    tris(trifluoroacetate);-   2-((1S)-1-{[(1-methylpiperidinium-4-yl)carbonyl]amino}-7-oxononyl)-6-phenylpyridinium    bis(trifluoroacetate);-   N-{(1S)-1-[5-(2-naphthyl)-1,3-oxazol-2-yl]-7-oxononyl}-2-(2-oxoquinazolin-1(2H)-yl)acetamide;-   3-(2-ethyl-1H-benzimidazol-1-yl)-N-{(1S)-1-[5-(2-naphthyl)-1,3-oxazol-2-yl]-7-oxononyl}propanamide;-   N,N-dimethyl-2-({(1S)-1-[5-(2-naphthyl)-1,3-oxazol-2-yl]-7-oxononyl}amino)-2-oxoethanaminium    trifluoroacetate;-   2-ethyl-1-(3-oxo-3-{[(1S)-7-oxo-1-(6-phenylpyridinium-2-yl)nonyl]amino}propyl)-1H-3,1-benzimidazol-1-ium    bis(trifluoroacetate);-   4-({[(1S)-7-oxo-1-(6-phenylpyridinium-2-yl)nonyl]amino}carbonyl)-1-azoniabicyclo[2.2.2]octane    bis(trifluoroacetate);-   2-((1S)-1-{[(benzylamino)carbonyl]amino}-7-oxononyl)-6-phenylpyridinium    trifluoroacetate;-   2-((1S)-7-[methoxy(methyl)amino]-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-quinoxalin-2-yl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-(3-methoxy-2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-{[benzyl(methyl)ammonio]methyl}-2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   2-{[2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]methyl}-1,2,3,4-tetrahydroisoquinolinium    bis(trifluoroacetate);-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxodecyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-(2-methoxyphenyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-(3-methoxyphenyl)-1H-imidazol-3-ium    trifluoroacetate;-   6-[2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium-5-yl]quinolinium    bis(trifluoroacetate);-   5-[2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium-5-yl]-2-methylquinolinium    bis(trifluoroacetate);-   5-[2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium-5-yl]quinolinium    bis(trifluoroacetate);-   5-[2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium-5-yl]-8-methylquinolinium    bis(trifluoroacetate);-   8-methoxy-5-[2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium-5-yl]quinolinium    bis(trifluoroacetate);-   5-(1-benzothien-7-yl)-2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium    trifluoroacetate;-   5-(1H-indol-5-yl)-2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium    trifluoroacetate;-   5-[3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl]-2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium    trifluoroacetate;-   5-(3-methoxy-2-naphthyl)-2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   2-((1S)-1-{[(2-ethyl-5-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-5-quinoxalin-2-yl-1H-imidazol-1-ium    bis(trifluoroacetate);-   2-((1S)-1-{[(2-ethyl-6-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   5-[4-(dimethylammonio)phenyl]-2-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   5-(2-fluoro-4-methoxyphenyl)-2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-(3-fluoro-4-methoxyphenyl)-2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-(3-carboxyphenyl)-2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-biphenyl-2-yl-2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-dibenzo[b,d]furan-4-yl-2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-[3-(piperidin-1-ylcarbonyl)phenyl]-1H-imidazol-1-ium    trifluoroacetate;-   2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-quinoxalin-6-yl-1H-imidazol-1-ium    trifluoroacetate;-   5-[(dimethylammonio)methyl]-2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   5-(1,4-dimethoxy-2-naphthyl)-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-{[2-(methylthio)ethyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-7-(methoxyamino)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-7-(ethoxyamino)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(2-methyl-5-nitro-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-inden-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(5-hydroxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[3-(5-methoxy-1H-benzimidazol-2-yl)propanoyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-1-[(1-benzothien-3-ylacetyl)amino]-7-oxononyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(2,5-dimethyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[3-(1H-benzimidazol-2-yl)propanoyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(6-methoxy-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-1-[(1H-indol-6-ylacetyl)amino]-7-oxononyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(2-methyl-1,3-benzothiazol-5-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[3-(5-methoxy-2-oxo-1,3-benzoxazol-3(2H)-yl)propanoyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[3-(7-methoxy-1H-indol-3-yl)propanoyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[3-(1,3-benzothiazol-2-yl)propanoyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(6-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(benzylamino)carbonyl]amino}-7-oxononyl)-4-phenylpyridinium    trifluoroacetate;-   4-({[(1S)-7-oxo-1-(4-phenylpyridinium-2-yl)nonyl]amino}carbonyl)-1-azoniabicyclo[2.2.2]octane    bis(trifluoroacetate);-   2-((1S)-1-{[2-(dimethylammonio)-2-methylpropanoyl]amino}-7-oxononyl)-4-phenylpyridinium    bis(trifluoroacetate);-   5-(3,5-dimethoxy-2-naphthyl)-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(benzyloxy)carbonyl]amino}-7-oxononyl)-4-phenylpyridinium    trifluoroacetate;-   2-((1S)-1-{([(1-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(7-fluoro-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(5-ethyl-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-(5-tert-butyl-2-methyl-1H-indol-3-yl)-N-[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-2-yl)nonyl]acetamide;-   2-((1S)-1-{[(5-ethoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-[5-(benzyloxy)-2-methyl-1H-indol-3-yl]-N-[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-2-yl)nonyl]acetamide;-   3-(1H-indol-1-yl)-N-[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-2-yl)nonyl]propanamide;-   2-((1S)-1-{[(5-methoxy-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-7-oxo-1-{[3-(2-oxo-1,3-benzothiazol-3(2H)-yl)propanoyl]amino}nonyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-7-oxo-1-[(quinolin-3-ylacetyl)amino]nonyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-7-oxo-1-[(quinolin-5-ylacetyl)amino]nonyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[3-(6-chloro-1H-benzimidazol-2-yl)propanoyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[3-(6-fluoro-1H-benzimidazol-2-yl)propanoyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   N-[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-2-yl)nonyl]-2-(5,6,7,8-tetrahydronaphthalen-1-yl)acetamide;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-8-methyl-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-6-carboxy-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}hexyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-(2-thienyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-(1-naphthyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-quinolin-8-yl-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-(2-morpholin-4-ylphenyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-(3-nitrophenyl)-1H-imidazol-3-ium    trifluoroacetate;-   3-[2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium-5-yl]pyridinium    bis(trifluoroacetate);-   5-(3-cyanophenyl)-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-[3-(trifluoromethoxy)phenyl]-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-[4-(trifluoromethyl)phenyl]-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-[3-(trifluoromethyl)phenyl]-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-[2-(trifluoromethyl)phenyl]-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-[2-fluoro-phenyl]-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-[3-(ethoxy)phenyl]-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-[4-(ethoxy)phenyl]-1H-imidazol-3-ium    trifluoroacetate;-   5-[4-(acetylamino)phenyl]-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium    trifluoroacetate;-   5-[2-(methoxycarbonyl)phenyl]-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-[4-cyano-phenyl]-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[5-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentanoyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   6-(2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)nonyl]amino}ethyl)imidazo[2,1-b][1,3]thiazol-4-ium    bis(trifluoroacetate);-   2-{(1S)-1-[(1-benzofuran-5-ylacetyl)amino]-7-oxononyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-1-[(1-benzothien-2-ylacetyl)amino]-7-oxononyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(2-ethyl-1H-benzimidazol-1-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-[2-((1S)-1-{[3-(dimethylammonio)propanoyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]-4-methoxyquinolinium    tris(trifluoroacetate);-   5-(4-chlorophenyl)-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-(3,4-dichlorophenyl)-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-(3-bromophenyl)-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-7-methoxy-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-(2-phenylethyl)-1H-imidazol-1-ium    trifluoroacetate;-   7-(3-oxo-3-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)nonyl]amino}propyl)-1,8-naphthyridin-1-ium    bis(trifluoroacetate);-   7-(3-oxo-3-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)nonyl]amino}propyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-1-ium    bis(trifluoroacetate);-   N³,N³-dimethyl-N-[{(1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}-α-alaninamide;-   2-{(1S)-7-oxo-1-[(4,5,6,7-tetrahydro-1H-indazol-3-ylcarbonyl)amino]nonyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-7-oxo-1-[(4,5,6,7-tetrahydro-1-benzothien-3-ylcarbonyl)amino]nonyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-7-oxo-1-{[3-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl]amino}nonyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-{(1S)-1-[({2-[2-(dimethylammonio)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}carbonyl)amino]-7-oxononyl}-5-phenyl-1H-imidazol-1-ium    bis(trifluoroacetate);-   6-benzyl-2-oxo-3-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)nonyl]amino}carbonyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridin-6-ium    bis(trifluoroacetate);-   7-(4-oxo-4-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)nonyl]amino}butanoyl)-6,7,8,9-tetrahydropyrido[2,3-b]-1,6-naphthyridin-1-ium    bis(trifluoroacetate);-   2-((1S)-1-{[(2-acetyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-methyl-3-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)nonyl]amino}carbonyl)-1,2,3,4-tetrahydroisoquinolinium    bis(trifluoroacetate);-   2-(2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)nonyl]amino}ethyl)-1,2,3,4-tetrahydroisoquinolinium    bis(trifluoroacetate);-   4-[2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium-5-yl]pyridinium    bis(trifluoroacetate);-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-(2-nitrophenyl)-1H-imidazol-3-ium    trifluoroacetate;-   5-(3-ammoniophenyl)-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium    bis(trifluoroacetate);-   5-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium    trifluoroacetate;-   5-(2,4-dimethoxyphenyl)-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium    trifluoroacetate;-   5-[2-fluoro-5-(trifluoromethyl)phenyl]-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium    trifluoroacetate;-   5-[3-(ammoniomethyl)phenyl]-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium    bis(trifluoroacetate);-   5-[2-(ammoniomethyl)-4-fluorophenyl]-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium    bis(trifluoroacetate);-   5-biphenyl-3-yl-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium    trifluoroacetate;-   3-[2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium-5-yl]quinolinium    bis(trifluoroacetate);-   5-(3-carboxyphenyl)-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-[3-(1H-tetrazol-5-yl)phenyl]-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-(3-{[(methylsulfonyl)amino]carbonyl}phenyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1R)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   2-[(1S)-1-({[1-(2-tert-butoxy-2-oxoethyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetyl}amino)-7-oxononyl]-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-[(1S)-1-({[5-methoxy-2-methyl-1-(pyridin-3-ylmethyl)-1H-indol-3-yl]acetyl}amino)-7-oxononyl]-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-1,2-dimethyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-[(1S)-1-({[5-methoxy-2-methyl-1-(2-pyrrolidinium-1-ylethyl)-1H-indol-3-yl]acetyl}amino)-7-oxononyl]-5-phenyl-1H-imidazol-1-ium    bis(trifluoroacetate);-   4-{2-[5-methoxy-2-methyl-3-(2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)nonyl]amino}ethyl)-1H-indol-1-yl]ethyl}morpholin-4-ium    bis(trifluoroacetate);-   2-((1S)-1-{[(5-methyl-1,2-benzisoxazol-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-[(1S)-1-({[5-(dimethylammonio)-2-methyl-1H-indol-3-yl]acetyl}amino)-7-oxononyl]-5-phenyl-1H-imidazol-1-ium    bis(trifluoroacetate);-   1-methyl-4-[({(1S)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxoundecyl}amino)carbonyl]piperidinium    bis(trifluoroacetate);-   1-methyl-4-[({(1S)-1-[5-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxodecyl}amino)carbonyl]piperidinium    bis(trifluoroacetate);-   N-[1-(5-acetyl-1H-imidazol-2-yl)-7-oxononyl]-2-(5-methoxy-2-methyl-1H-indol-3-yl)acetamide;-   2-[2-((1S)-1-{[3-(dimethylammonio)propanoyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]-4-methoxyquinolinium    trichloride;-   2-((1S)-1-{[(6-methoxy-1-benzofuran-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   6-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)nonyl]amino}carbonyl)quinolinium    bis(trifluoroacetate);-   6-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)nonyl]amino}carbonyl)isoquinolinium    bis(trifluoroacetate);-   5-methyl-6-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)nonyl]amino}carbonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-3,5-diium    tris(trifluoroacetate);-   2-(5-methyl-1-benzothien-3-yl)-N-[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-2-yl)nonyl]acetamide;-   2-[(1S)-1-({[1-(carboxymethyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetyl}amino)-7-oxononyl]-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   4-{[5-methoxy-2-methyl-3-(2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)nonyl]amino}ethyl)-1H-indol-1-yl]acetyl}-1-methylpiperazin-1-ium    bis(trifluoroacetate);-   7-methyl-2-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)nonyl]amino}carbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-4,7-diium    tris(trifluoroacetate);-   2-{(1S)-1-[({5-[(dimethylammonio)methyl]-2-methyl-1H-indol-3-yl}acetyl)amino]-7-oxononyl}-5-phenyl-1H-imidazol-1-ium    bis(trifluoroacetate);-   5-bromo-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium    trifluoroacetate;-   5-(4-carboxyphenyl)-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium    trifluoroacetate;-   5-(3-hydroxyphenyl)-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-[2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]isoquinolinium    bis(trifluoroacetate);-   5-{4-[(dimethylammonio)methyl]phenyl}-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   4-methoxy-2-[2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]quinolinium    tris(trifluoroacetate);-   5-(2-carboxyphenyl)-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    trifluoroacetate;-   5-[4-(dimethylammonio)phenyl]-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   2-((1S)-7-oxo-1-{[(4,5,6,7-tetrafluoro-1H-indol-3-yl)acetyl]amino}nonyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(5-fluoro-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   1-methyl-N-{(1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}azetidine-3-carboxamide;-   2-{(1S)-7-oxo-1-[(1H-pyrrolo[2,3-b]pyridin-3-ylacetyl)amino]nonyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   4-({[(1S)-6-carboxy-1-(5-phenyl-1H-imidazol-1-ium-2-yl)hexyl]amino}carbonyl)-1-azoniabicyclo[2.2.2]octane    bis(trifluoroacetate);-   4-({[(1S)-7-(methoxyamino)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)heptyl]amino}carbonyl)-1-azoniabicyclo[2.2.2]octane    bis(trifluoroacetate);-   1-methyl-4-({[(1S)-7-oxo-1-(4-phenyl-1H-imidazol-3-ium-2-yl)-7-(2-thienyl)heptyl]amino}carbonyl)piperidinium    bis(trifluoroacetate);-   2-{(1S)-7-oxo-1-[(1H-pyrrolo[3,2-c]pyridin-3-ylacetyl)amino]nonyl}-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   2-((1S)-1-{[(5-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium    trifluoroacetate;-   5-(2-fluoroquinolin-3-yl)-2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-3-ium    bis(trifluoroacetate);-   2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-5-quinoxalin-6-yl-1H-imidazol-3-ium    bis(trifluoroacetate);-   8-methoxy-5-[2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-3-ium-5-yl]quinolinium    tris(trifluoroacetate);-   5-[4-(dimethylamino)phenyl]-2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-3-ium    bis(trifluoroacetate);-   2-methyl-1-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)nonyl]amino}carbonyl)-1,2,3,4-tetrahydroisoquinolinium    bis(trifluoroacetate);-   5-(3-carboxyphenyl)-2-{(1S)-7-oxo-1-[(2-thienylcarbonyl)amino]nonyl}-1H-imidazol-3-ium    trifluoroacetate;-   4-methoxy-2-(2-{(1S)-1-[(3-morpholin-4-ium-4-ylpropanoyl)amino]-7-oxononyl}-1H-imidazol-1-ium-5-yl)quinolinium    trichloride;-   2-[2-((1S)-1-{[3-(1H-imidazol-1-ium-1-yl)propanoyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]-4-methoxyquinolinium    trichloride;-   2-[2-((1S)-1-{[(4-acetylpiperazin-1-ium-1-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]-4-methoxyquinolinium    trichloride;-   2-[2-((1S)-1-{[(dimethylammonio)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]-4-methoxyquinolinium    trichloride;-   4-methoxy-2-(2-{(1S)-7-oxo-1-[(piperidinium-1-ylacetyl)amino]nonyl}-1H-imidazol-1-ium-5-yl)quinolinium    trichloride;-   4-methoxy-2-[2-((1S)-1-{[(4-methylpiperazin-4-ium-1-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]quinolinium    trichloride;-   4-methoxy-2-[2-((1S)-1-{[(4-methylmorpholin-4-ium-2-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]quinolinium    tris(trifluoroacetate);-   4-methoxy-2-[2-((S)-1-{[3-(4-methylpiperazin-4-ium-1-yl)propanoyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]quinolinium    tris(trifluoroacetate);-   4-methoxy-2-[2-((1S)-1-{[(4-methylpiperazin-4-ium-1-yl)(oxo)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]quinolinium    tris(trifluoroacetate);-   2-[(1S)-1-({[1-(N,N-dimethylglycyl)azetidin-3-yl]carbonyl}amino)-7-oxononyl]-5-(4-methoxyquinolin-2-yl)-1H-imidazol-1-ium    trifluoroacetate;-   2-[(1S)-1-({[1-(2-methoxyethyl)azetidinium-3-yl]carbonyl}amino)-7-oxononyl]-5-(4-methoxyquinolin-2-yl)-1H-imidazol-1-ium    bis(trifluoroacetate);-   1-methyl-3-[({(1S)-1-[5-(1,8-naphthyridin-2-yl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}amino)carbonyl]azetidinium    formate;-   1-methyl-3-[({(1S)-1-[5-(1,6-naphthyridin-2-yl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}amino)carbonyl]azetidinium    formate;-   1-methyl-3-[({(1S)-1-[5-(1,6-naphthyridin-8-yl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}amino)carbonyl]azetidinium    formate;-   3-({(1S)-1-[5-(4-methoxyquinolin-2-yl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}amino)-N,N-dimethyl-3-oxopropan-1-aminium    formate;-   4-[({(1S)-1-[5-(4-methoxyquinolin-2-yl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}amino)carbonyl]-1-azoniabicyclo[2.2.2]octane    formate;-   2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-5-(2-oxo-1,2-dihydroquinolin-3-yl)-1H-imidazol-3-ium    bis(trifluoroacetate);-   N-{(S)-1-[5-(4-methoxyquinolin-2-yl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}-2-(1H-pyrrolo[3,2-c]pyridin-3-yl)acetamide;-   5-(4-methoxyquinolin-2-yl)-2-{(1S)-7-oxo-1-[(1H-pyrrolo[3,2-c]pyridin-3-ylacetyl)amino]nonyl}-1H-imidazol-1-ium    trifluoroacetate;-   5-(3-carboxyphenyl)-2-((1S)-1-{[(1-methylpiperidin-4-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-3-ium    trifluoroacetate;-   5-(3-carboxyphenyl)-2-{(1S)-1-[(morpholin-4-ylacetyl)amino]-7-oxononyl}-1H-imidazol-3-ium    trifluoroacetate;-   5-(3-carboxyphenyl)-2-{(1S)-1-[(N,N-dimethylglycyl)amino]-7-oxononyl}-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[(1-methylpiperidin-4-yl)carbonyl]amino}-7-oxononyl)-5-(3-{[(methylsulfonyl)amino]carbonyl}phenyl)-1H-imidazol-3-ium    trifluoroacetate;-   2-((1S)-1-{[3-(3-methoxyazetidinium-1-yl)propanoyl]amino}-7-oxononyl)-5-quinoxalin-6-yl-1H-imidazol-1-ium    bis(trifluoroacetate);-   3-({[(1S)-7-oxo-1-(5-quinoxalin-6-yl-1H-imidazol-3-ium-2-yl)nonyl]amino}carbonyl)-1-azoniabicyclo[2.2.2]octane    bis(trifluoroacetate);-   4-({[(1S)-7-Oxo-1-(5-quinoxalin-6-yl-1H-imidazol-1-ium-2-yl)nonyl]amino}carbonyl)-1-azoniabicyclo[2.2.2]octane    bis(trifluoroacetate);-   5-(2-methoxyquinolin-3-yl)-2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-3-ium    dichloride;-   2-((1S)-1-{[(dimethylammonio)acetyl]amino}-7-oxononyl)-5-(4-methoxyquinolin-2-yl)-1H-imidazol-1-ium    dichloride;-   3-[({(1S)-1-[5-(2-methoxyquinolin-3-yl)-1H-imidazol-2-yl]-7-oxononyl}amino)carbonyl]-1-methylazetidinium    chloride;-   N-{(1S)-1-[5-(2-methoxyquinolin-3-yl)-1H-imidazol-2-yl]-7-oxononyl}-1-methylazetidine-3-carboxamide;-   N-{(1S)-7-[methoxy(methyl)amino]-1-[5-(2-methoxyquinolin-3-yl)-1H-imidazol-2-yl]-7-oxoheptyl}-1-methylazetidine-3-carboxamide;    and the pharmaceutically acceptable free bases, salts, alternative    salts and stereoisomers thereof.

Included in the instant invention is the free base of compounds ofFormula I, as well as the pharmaceutically acceptable salts andstereoisomers thereof. Some of the specific compounds exemplified hereinare the protonated salts of amine compounds. Compounds of Formula I witha heterocycle ring containing 2 or more N atoms may be protonated on anyone, some or all of the N atoms. The term “free base” refers to theamine compounds in non-salt form. The encompassed pharmaceuticallyacceptable salts not only include the salts exemplified for the specificcompounds described herein, but also all the typical pharmaceuticallyacceptable salts of the free form of compounds of Formula I. The freeform of the specific salt compounds described may be isolated usingtechniques known in the art. For example, the free form may beregenerated by treating the salt with a suitable dilute aqueous basesolution such as dilute aqueous NaOH, potassium carbonate, ammonia andsodium bicarbonate. The free forms may differ from their respective saltforms somewhat in certain physical properties, such as solubility inpolar solvents, but the acid and base salts are otherwisepharmaceutically equivalent to their respective free forms for purposesof the invention.

The pharmaceutically acceptable salts of the instant compounds can besynthesized from the compounds of this invention which contain a basicor acidic moiety by conventional chemical methods. Generally, the saltsof the basic compounds are prepared either by ion exchangechromatography or by reacting the free base with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidin a suitable solvent or various combinations of solvents. Similarly,the salts of the acidic compounds are formed by reactions with theappropriate inorganic or organic base.

Thus, pharmaceutically acceptable salts of the compounds of thisinvention include the conventional non-toxic salts of the compounds ofthis invention as formed by reacting a basic instant compound with aninorganic or organic acid. For example, conventional non-toxic saltsinclude those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, aswell as salts prepared from organic acids such as acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroaceticand the like. Preferably, a pharmaceutically acceptable salt of thisinvention contains 1 equivalent of a compound of formula (I) and 1, 2 or3 equivalent of an inorganic or organic acid. More particularly,pharmaceutically acceptable salts of this invention are thetrifluoroacetate or the chloride salts, especially the trifluoroacetatesalts. Preferably, pharmaceutically acceptable salts of this inventionare the tartrate salts.

When the compound of the present invention is acidic, suitable“pharmaceutically acceptable salts” refers to salts prepared formpharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as arginine, betainecaffeine, choline, N,N′-dibenzylethylenediamine, diethylamin,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylaminetripropylamine, tromethamine and the like.

The preparation of the pharmaceutically acceptable salts described aboveand other typical pharmaceutically acceptable salts is more fullydescribed by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977:66:1-19.

It will also be noted that the compounds of the present invention arepotentially internal salts or zwitterions, since under physiologicalconditions a deprotonated acidic moiety in the compound, such as acarboxyl group, may be anionic, and this electronic charge might then bebalanced off internally against the cationic charge of a protonated oralkylated basic moiety, such as a quaternary nitrogen atom.

The compounds of the invention can be used in a method of treatment ofthe human or animal body by therapy.

The compounds of the invention find use in a variety of applications forhuman and animal health. The compounds of the invention are histonedeacetylase (HDAC) inhibitors useful in the treatment of cancer amongother diseases. HDACs catalyse the removal of acetyl groups from lysineresidues on proteins, including histones and HDAC inhibitors showdiverse biological functions including affecting gene expression, celldifferentiation, cell cycle progression, growth arrest, and/orapoptosis. See J. Med. Chem. 2003, 46:5097 and Curr. Med. Chem. 2003,10:2343.

The compounds of the invention are used to treat cellular proliferationdiseases. Disease states which can be treated by the methods andcompositions provided herein include, but are not limited to, cancer(further discussed below), neurodegenerative diseases, schizophrenia andstroke

The compounds, compositions and methods provided herein are particularlydeemed useful for the treatment of cancer including solid tumors such asskin, breast, brain, cervical carcinomas, testicular carcinomas, etc. Inparticular, cancers that may be treated by the compounds, compositionsand methods of the invention include, but are not limited to: Cardiac:sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma),myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogeniccarcinoma (squamous cell, undifferentiated small cell, undifferentiatedlarge cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchialadenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel(adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor[nephroblastoma], lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenicsarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma,osteitis deformans), meninges (meningioma, meningiosarcoma,gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma,germinoma [pinealoma], glioblastoma multiform, oligodendroglioma,schwannoma, retinoblastoma, congenital tumors), spinal cordneurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acuteand chronic], acute lymphoblastic leukemia, chronic lymphocyticleukemia, myeloproliferative diseases, multiple myeloma, myelodysplasticsyndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignantlymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cellcarcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.Thus, the term “cancerous cell” as provided herein, includes a cellafflicted by any one of the above-identified conditions.

Thus, the present invention provides a compound of formula I for use inthe manufacture of a medicament for treating cellular proliferationdiseases.

The present invention also provides a method for the treatment ofcellular proliferation diseases, which method comprises administrationto a patient in need thereof of an effective amount of a compound offormula I or a composition comprising a compound of formula I.

The compounds of the instant invention may also be useful in thetreatment or prevention of neurodegenerative diseases, including, butnot limited to, polyglutamine-expansion-related neurodegeneration,Huntington's disease, Kennedy's disease, spinocerebellar ataxia,dentatorubral-pallidoluysian atrophy (DRPLA),protein-aggregation-related neurodegeneration, Machado-Joseph's disease,Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,spongiform encephalopathy, a prion-related disease and multiplesclerosis (MS). See WO 02/090534 and WO 03/083067.

Thus, the present invention provides a compound of formula I for use inthe manufacture of a medicament for treating or preventingneurodegenerative diseases.

The present invention also provides a method for treating or preventingneurodegenerative diseases, which method comprises administration to apatient in need thereof of an effective amount of a compound of formulaI or a composition comprising a compound of formula I.

The compounds of the invention may also be useful in the treatment orprevention of mental retardation, in particular “X chromosome-linkedmental retardation” and “Rubinstein-Taybi syndrome”.

Thus, the present invention provides a compound of formula I for themanufacture of a medicament for treating or preventing mentalretardation.

The present invention also provides a method for treating or preventingmental retardation, which method comprises administration to a patientin need thereof of an effective amount of a compound of formula I or acomposition comprising a compound of formula I.

The compounds of the invention may also be useful in the treatment orprevention of schizophrenia, see WO 02/090534.

Thus, the present invention provides a compound of formula I for themanufacture of a medicament for treating or preventing schizophrenia.

The present invention also provides a method for treating or preventingschizophrenia, which method comprises administration to a patient inneed thereof of an effective amount of a compound of formula I or acomposition comprising a compound of formula I.

The compounds of the invention may also be useful in the treatment orprevention of inflammatory diseases, including, but not limited tostroke, rheumatoid arthritis, lupus erythematosus, ulcerative colitisand traumatic brain injuries. See Leoni et al., PNAS, 99(5):2995-3000(2002), Suuronen et al., J. Neurochem. 87:407-416 (2003) and DrugDiscovery Today, 10: 197-204 (2005).

Thus, the present invention provides a compound of formula I for themanufacture of a medicament for treating or preventing inflammatorydiseases.

The present invention also provides a method for treating or preventinginflammatory diseases, which method comprises administration to apatient in need thereof of an effective amount of a compound of formulaI or a composition comprising a compound of formula I.

The compounds of the present invention are also useful in the inhibitionof smooth muscle cell proliferation and/or migration and are thus usefulin the prevention and/or treatment of restenosis, for example afterangioplasty and/or stent implantation.

Thus, the present invention provides a compound of formula I for themanufacture of a medicament for treating or preventing restenosis.

The present invention also provides a method for treating or preventionrestenosis, which method comprises administration to a patient in needthereof of an effective amount of a compound of formula I or acomposition comprising a compound of formula I.

In one embodiment, smooth muscle cell proliferation and/or migration isinhibited and restenosis is prevented and/or treated by providing astent device having one or more of the compounds of the instantinvention in or on the stent device, e.g. coated onto the stent device.The stent device is designed to controllably release the compounds ofthe invention, thereby inhibiting smooth miscle cell proliferationand/or migration and preventing and/or treating restenosis.

Stenosis and restenosis are conditions associated with a narrowing ofblood vessels. Stenosis of blood vessels generally occurs gradually overtime. Restenosis, in contrast, relates to a narrowing of blood vesselsfollowing an endovascular procedure, such as balloon angioplasty and/orstent implantation, or a vascular injury.

Balloon angioplasty is typically performed to open a stenotic bloodvessel; stenting is usually performed to maintain the patency of a bloodvessel after, or in combination with, balloon angioplasty. A stenoticblood vessel is opened with balloon angioplasty by navigating aballoon-tipped catheter to the site of stenosis, and expanding theballoon tip effectively to dilate the occluded blood vessel. In aneffort to maintain the patency of the dilated blood vessel, a stent maybe implanted in the blood vessel to provide intravascular support to theopened section of the blood vessel, thereby limiting the extent to whichthe blood vessel will return to its occluded state after release of theballoon catheter. Restenosis is typically caused by trauma inflictedduring angioplasty, effected by, for example, ballon dilation,atherectomy or laser ablation treatment of the artery. For theseprocedures, restenosis occurs at a rate of about 30% to about 60%depending on the vessel location, lesion length and a number of othervariables. This reduces the overall success of the relativelynon-invasive balloon angioplasty and stenting procedures

Restenosis is attributed to many factors, including proliferation ofsmooth muscle cells (SMC). SMC proliferation is triggered by the initialmechanical injury to the intima that is sustained at the time of balloonangioplasty and stent implantation. The process is characterized byearly platelet activation and thrombus formation, followed by SMCrecruitment and migration, and, finally, cellular proliferation andextracellular matrix accumulation. Damaged endothelial cells, SMCs,platelets, and macrophages secrete cytokines and growth factors whichpromote restenosis. SMC proliferation represents the final commonpathway leading to neointimal hyperplasia. Therefore, anti-proliferativetherapies aimed at inhibiting specific regulatory events in the cellcycle may constitute the most reasonable approach to restenosis afterangioplasty.

The compounds of the invention may also be used as immunosuppressants orimmunomodulators and can accordingly be used in the treatment orprevention of immune response or immune-mediated responses and diseasessuch as systemic lupus erythematosus (SLE) and acute or chronictransplant rejection in a recipient of an organ, tissue or celltransplant, (see WO 05/013958).

Examples of autoimmune diseases for which the compounds of the inventionmay be employed include autoimmune hematological disorders (includinghemolytic anaemia, aplastic anaemia, pure red cell anaemia andidiopathic thrombocytopenia), systemic lupus erythematosus, thyroiditis,Hashimoto's thyroiditis, polychondritis, sclerodoma, Wegenergranulamatosis, dermatomyositis, chronic active hepatitis, myastheniagravis, psoriasis, atopic dermatitis, vasculitis, Steven-Johnsonsyndrome, idiopathic sprue, autoimmune inflammatory bowel disease(including ulcerative colitis and Crohn's disease) endocrineopthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primarybilliary cirrhosis, juvenile diabetes (diabetes mellitus type I),diabetes type II and the disorders associated therewith, uveitis(anterior and posterior), keratoconjunctivitis sicca and vernalkeratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis,glomerulonephritis (with and without nephrotic syndrome, includingidiopathic nephrotic syndrome or minimal change nephropathy), juveniledermatomyositisinfectious, auto-antibody mediated diseases, aplasticanemia, Evan's syndrome, autoimmune hemolytic anemia, infectiousdiseases causing aberrant immune response and/or activation, such astraumatic or pathogen induced immune disregulation, including forexample, that which are caused by hepatitis B and C infections,staphylococcus aureus infection, viral encephalitis, sepsis, parasiticdiseases wherein damage is induced by inflammatory response (e.g.leprosy); and circulatory diseases, such as arteriosclerosis,atherosclerosis, polyarteritis nodosa and myocarditis.

Thus, the present invention provides a compound of formula I for themanufacture of a medicament for the treatment or prevention of immunedisorders.

The present invention also provides a method for treating or preventingimmune disorders, which method comprises administration to a patent inneed thereof of an effective amount of a compound of formula I or acomposition comprising a compound of formula I.

The compounds of the invention may also be useful in the treatment orprevention of other diseases such as diabetes, cardiovascular disordersand asthma.

The compounds of the invention may also be useful in the treatment orprevention of cardiac hypertrophy and heart failure, as described inCell, 110:479-488 (2002).

In an embodiment the compounds of this invention may be useful for thetreatment or prevention of neurodegenerative diseases, schizophrenia,stroke, mental retardation, immune disorders or asthma.

The compounds of this invention may be administered to mammals,preferably humans, either alone or in combination with pharmaceuticallyacceptable carriers, excipients or diluents, in a pharmaceuticalcomposition, according to standard pharmaceutical practice. In oneembodiment, the compounds of this invention may be administered toanimals. The compounds can be administered orally or parenterally,including the intravenous, intramuscular, intraperitoneal, subcutaneous,rectal and topical routes of administration.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention and a pharmaceutically acceptablecarrier. The pharmaceutical compositions containing the activeingredient may be in a form suitable for oral use, for example, astablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example,microcrystalline cellulose, sodium crosscarmellose, corn starch, oralginic acid; binding agents, for example starch, gelatin,polyvinyl-pyrrolidone or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be uncoated orthey may be coated by known techniques to mask the unpleasant taste ofthe drug or delay disintegration and absorption in the gastrointestinaltract and thereby provide a sustained action over a longer period. Forexample, a water soluble taste masking material such ashydroxypropyl-methylcellulose or hydroxypropylcellulose, or a time delaymaterial such as ethyl cellulose, cellulose acetate butyrate may beemployed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavoring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous solutions. Among the acceptable vehicles and solventsthat may be employed are water, Ringer's solution and isotonic sodiumchloride solution.

The sterile injectable preparation may also be a sterile injectableoil-in-water microemulsion where the active ingredient is dissolved inthe oily phase. For example, the active ingredient may be firstdissolved in a mixture of soybean oil and lecithin. The oil solutionthen introduced into a water and glycerol mixture and processed to forma microemulation.

The injectable solutions or microemulsions may be introduced into apatient's blood stream by local bolus injection. Alternatively, it maybe advantageous to administer the solution or microemulsion in such away as to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An example ofsuch a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension for intramuscular andsubcutaneous administration. This suspension may be formulated accordingto the known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butane diol. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

Compounds of Formula I may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compound of Formula I are employed. (For purposesof this application, topical application shall include mouth washes andgargles.)

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles anddelivery devices, or via transdermal routes, using those forms oftransdermal skin patches well known to those of ordinary skill in theart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen. Compounds of the presentinvention may also be delivered as a suppository employing bases such ascocoa butter, glycerinated gelatin, hydrogenated vegetable oils,mixtures of polyethylene glycols of various molecular weights and fattyacid esters of polyethylene glycol.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, sex and response of the individual patient, as well as theseverity of the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer. Administrationgenerally occurs in an amount between about 0.1 mg/kg of body weight toabout 60 mg/kg of body weight per day, preferably of between 0.5 mg/kgof body weight to about 40 mg/kg of body weight per day.

The instant compounds are also useful in combination with knowntherapeutic agents and anti-cancer agents. Thus, this invention providescombinations of compounds of formula (I) and known therapeutic agentsand/or anti-cancer agents for simultaneous, separate or sequentialadministration. For example, instant compounds are useful in combinationwith known anti-cancer agents. Combinations of the presently disclosedcompounds with other anti-cancer or chemotherapeutic agents are withinthe scope of the invention. Examples of such agents can be found inCancer Principles and Practice of Oncology by V. T. Devita and S.Hellman (editors), 6^(th) edition (Feb. 15, 2001), Lippincott Williams &Wilkins Publishers. A person of ordinary skill in the art would be ableto discern which combinations of agents would be useful based on theparticular characteristics of the drugs and the cancer involved. Suchanti-cancer agents include, but are not limited to, the following: otherHDAC inhibitors, estrogen receptor modulators, androgen receptormodulators, retinoid receptor modulators, cytotoxic/cytostatic agents,antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoAreductase inhibitors and other angiogenesis inhibitors, inhibitors ofcell proliferation and survival signaling, apoptosis inducing agents andagents that interfere with cell cycle checkpoints. The instant compoundsare particularly useful when co-administered with radiation therapy.

In an embodiment, the instant compounds are also useful in combinationwith known anti-cancer agents including the following: other HDACinhibitors, estrogen receptor modulators, androgen receptor modulators,retinoid receptor modulators, cytotoxic agents, antiproliferativeagents, prenyl-protein transferase inhibitors, HMG-CoA reductaseinhibitors, HIV protease inhibitors, reverse transcriptase inhibitors,and other angiogenesis inhibitors.

Examples of “other HDAC inhibitors” include suberoylanilide hydroxamicacid (SAHA), LAQ824, LBH589, PXD101, MS275, FK228, valproic acid,butyric acid and CI-994.

“Estrogen receptor modulators” refers to compounds that interfere withor inhibit the binding of estrogen to the receptor, regardless ofmechanism. Examples of estrogen receptor modulators include, but are notlimited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

“Androgen receptor modulators” refers to compounds which interfere orinhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole, and abiraterone acetate.

“Retinoid receptor modulators” refers to compounds which interfere orinhibit the binding of retinoids to the receptor, regardless ofmechanism. Examples of such retinoid receptor modulators includebexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, ILX23-7553, trans-N-(4′-hydroxyphenyl)retinamide, and N-4-carboxyphenyl retinamide.

“Cytotoxic/cytostatic agents” refer to compounds which cause cell deathor inhibit cell proliferation primarily by interfering directly with thecell's functioning or inhibit or interfere with cell mytosis, includingalkylating agents, tumor necrosis factors, intercalators, hypoxiaactivatable compounds, microtubule inhibitors/microtubule-stabilizingagents, inhibitors of mitotic kinesins, inhibitors of kinases involvedin mitotic progression, antimetabolites; biological response modifiers;hormonal/anti-hormonal therapeutic agents, haematopoietic growthfactors, monoclonal antibody targeted therapeutic agents, topoisomeraseinhibitors, proteasome inhibitors and ubiquitin ligase inhibitors.

Examples of cytotoxic agents include, but are not limited to, sertenef,cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine,prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin,oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfantosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa,lobaplatin, satraplatin, profiromycin, cisplatin, irofulven,dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum,benzylguanine, glufosfamide, GPX100, (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarizidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycaminomycin, annamycin,galarubicin, elinafide, MEN10755, and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin (seeWO 00/50032).

An example of a hypoxia activatable compound is tirapazamine.

Examples of proteasome inhibitors include but are not limited tolactacystin, bortezomib, epoxomicin and peptide aldehydes such as MG132, MG 115 and PSI.

In an embodiment, the compounds of the present invention may be used incombination with other HDAC inhibitors such as SAHA and proteasomeinhibitors.

Examples of microtubule inhibitors/microtubule-stabilising agentsinclude paclitaxel, vindesine sulfate,3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol, rhizoxin,dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881,BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and6,288,237) and BMS188797.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]-indolizino[1,2b]quinoline-10,13(9H,15H)dione,lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350,BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,(5a,5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-bexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium,6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one,and dimesna.

Examples of inhibitors of mitotic kinesins, and in particular the humanmitotic kinesin KSP, are described in PCT Publications WO 01/30768, WO01/98278, WO 02/056880, WO 03/050,064, WO 03/050,122, WO 03/049,527, WO03/049,679, WO 03/049,678, WO 03/039460, WO 03/079973, WO 03/099211, WO2004/039774, WO 03/105855, WO 03/106417, WO 2004/087050, WO 2004/058700,WO 2004/058148 and WO 2004/037171 and US applications US 2004/132830 andUS 2004/132719. In an embodiment inhibitors of mitotic kinesins include,but are not limited to inhibitors of KSP, inhibitors of MKLP1,inhibitors of CENP-E, inhibitors of MCAK, inhibitors of Kif14,inhibitors of Mphosph1 and inhibitors of Rab6-KIFL.

“Inhibitors of kinases involved in mitotic progression” include, but arenot limited to, inhibitors of aurora kinase, inhibitors of Polo-likekinases (PLK) (in particular inhibitors of PLK-1), inhibitors of bub-1and inhibitors of bub-R1.

“Antiproliferative agents” includes antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-fluorouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,1′-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N4-palmitoyl-1-B-D-arabino furanosyl cytosine and3-aminopyridine-2-carboxaldehyde thiosemicarbazone.

Examples of monoclonal antibody targeted therapeutic agents includethose therapeutic agents which have cytotoxic agents or radioisotopesattached to a cancer cell specific or target cell specific monoclonalantibody. Examples include Bexxar.

“HMG-CoA reductase inhibitors” refers to inhibitors of3-hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductaseinhibitors that may be used include but are not limited to lovastatin(MEVACOR®; see U.S. Pat. Nos. 4,231,938, 4,294,926 and 4,319,039),simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850 and4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat. Nos. 4,346,227,4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL®;see U.S. Pat. Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164,5,118,853, 5,290,946 and 5,356,896) and atorvastatin (LIPITOR®; see U.S.Pat. Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952). The structuralformulas of these and additional HMG-CoA reductase inhibitors that maybe used in the instant methods are described at page 87 of M. Yalpani,“Cholesterol Lowering Drugs”, Chemistry & Industry, pp. 85-89 (5 Feb.1996) and U.S. Pat. Nos. 4,782,084 and 4,885,314. The term HMG-CoAreductase inhibitor as used herein includes all pharmaceuticallyacceptable lactone and open-acid forms (i.e., where the lactone ring isopened to form the free acid) as well as salt and ester forms ofcompounds which have HMG-CoA reductase inhibitory activity, and thereforthe use of such salts, esters, open-acid and lactone forms is includedwithin the scope of this invention.

“Prenyl-protein transferase inhibitor” refers to a compound whichinhibits any one or any combination of the prenyl-protein transferaseenzymes, including farnesyl-protein transferase (FPTase),geranylgeranyl-protein transferase type I (GGPTase-I), andgeranylgeranyl-protein transferase type-II (GGPTase-II, also called RabGGPTase).

Examples of prenyl-protein transferase inhibitors can be found in thefollowing publications and patents: WO 96/30343, WO 97/18813, WO97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO95/32987, U.S. Pat. No. 5,420,245, U.S. Pat. No. 5,523,430, U.S. Pat.No. 5,532,359, U.S. Pat. No. 5,510,510, U.S. Pat. No. 5,589,485, U.S.Pat. No. 5,602,098, European Patent Publ. 0 618 221, European PatentPubl. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ.0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO 96/33159, WO96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO98/02436, and U.S. Pat. No. 5,532,359. For an example of the role of aprenyl-protein transferase inhibitor on angiogenesis see European J. ofCancer, Vol. 35, No. 9, pp. 1394-1401 (1999).

“Angiogenesis inhibitors” refers to compounds that inhibit the formationof new blood vessels, regardless of mechanism. Examples of angiogenesisinhibitors include, but are not limited to, tyrosine kinase inhibitors,such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) andFlk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived,or platelet derived growth factors, MMP (matrix metalloprotease)inhibitors, integrin blockers, interferon-α, interleukin-12, pentosanpolysulfate, cyclooxygenase inhibitors, including nonsteroidalanti-inflammatories (NSAIDs) like aspirin and ibuprofen as well asselective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib(PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch.Opthalmol., Vol. 108, p. 573 (1990); Anat. Rec., Vol. 238, p. 68 (1994);FEBS Letters, Vol. 372, p. 83 (1995); Clin, Orthop. Vol. 313, p. 76(1995); J. Mol. Endocrinol., Vol. 16, p. 107 (1996); Jpn. J. Pharmacol.,Vol. 75, p. 105 (1997); Cancer Res., Vol. 57, p. 1625 (1997); Cell, Vol.93, p. 705 (1998); Intl. J. Mol. Med., Vol. 2, p. 715 (1998); J. Biol.Chem., Vol. 274, p. 9116 (1999)), steroidal anti-inflammatories (such ascorticosteroids, mineralocorticoids, dexamethasone, prednisone,prednisolone, methylpred, betamethasone), carboxyamidotriazole,combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol,thalidomide, angiostatin, troponin-1, angiotensin II antagonists (seeFernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and antibodiesto VEGF (see, Nature Biotechnology, Vol. 17, pp. 963-968 (October 1999);Kim et al., Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186).

Other therapeutic agents that modulate or inhibit angiogenesis and mayalso be used in combination with the compounds of the instant inventioninclude agents that modulate or inhibit the coagulation and fibrinolysissystems (see review in Clin. Chem. La. Med. 38:679-692 (2000)). Examplesof such agents that modulate or inhibit the coagulation and fibrinolysispathways include, but are not limited to, heparin (see Thromb. Haemost.80:10-23 (1998)), low molecular weight heparins and carboxypeptidase Uinhibitors (also known as inhibitors of active thrombin activatablefibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101:329-354(2001)). TAFIa inhibitors have been described in PCT Publication WO03/013,526 and U.S. Ser. No. 60/349,925 (filed Jan. 18, 2002).

“Agents that interfere with cell cycle checkpoints” refer to compoundsthat inhibit protein kinases that transduce cell cycle checkpointsignals, thereby sensitizing the cancer cell to DNA damaging agents.Such agents include inhibitors of ATR, ATM, the Chk1 and Chk2 kinasesand cdk and cdc kinase inhibitors and are specifically exemplified by7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.

“Inhibitors of cell proliferation and survival signaling pathway” referto pharmaceutical agents that inhibit cell surface receptors and signaltransduction cascades downstream of those surface receptors. Such agentsinclude inhibitors of inhibitors of EGFR (for example gefitinib anderlotinib), inhibitors of ERB-2 (for example trastuzumab), inhibitors ofIGFR (for example those disclosed in WO 03/059951), inhibitors ofcytokine receptors, inhibitors of MET, inhibitors of PI3K (for exampleLY294002), serine/threonine kinases (including but not limited toinhibitors of Akt such as described in (WO 03/086404, WO 03/086403, WO03/086394, WO 03/086279, WO 02/083675, WO 02/083139, WO 02/083140 and WO02/083138), inhibitors of Raf kinase (for example BAY43-9006),inhibitors of MEK (for example CI-1040 and PD-098059) and inhibitors ofmTOR (for example Wyeth CCI-779 and Ariad AP23573). Such agents includesmall molecule inhibitor compounds and antibody antagonists.

“Apoptosis inducing agents” include activators of TNF receptor familymembers (including the TRAIL receptors).

The invention also encompasses combinations with NSAID's which areselective COX-2 inhibitors. For purposes of this specification NSAID'swhich are selective inhibitors of COX-2 are defined as those whichpossess a specificity for inhibiting COX-2 over COX-1 of at least 100fold as measured by the ratio of IC₅₀ for COX-2 over IC₅₀ for COX-1evaluated by cell or microsomal assays. Such compounds include, but arenot limited to those disclosed in U.S. Pat. No. 5,474,995, U.S. Pat. No.5,861,419, U.S. Pat. No. 6,001,843, U.S. Pat. No. 6,020,343, U.S. Pat.No. 5,409,944, U.S. Pat. No. 5,436,265, U.S. Pat. No. 5,536,752, U.S.Pat. No. 5,550,142, U.S. Pat. No. 5,604,260, U.S. Pat. No. 5,698,584,U.S. Pat. No. 5,710,140, WO 94/15932, U.S. Pat. No. 5,344,991, U.S. Pat.No. 5,134,142, U.S. Pat. No. 5,380,738, U.S. Pat. No. 5,393,790, U.S.Pat. No. 5,466,823, U.S. Pat. No. 5,633,272, and U.S. Pat. No.5,932,598, all of which are hereby incorporated by reference.

Inhibitors of COX-2 that are particularly useful in the instant methodof treatment are5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine; ora pharmaceutically acceptable salt thereof.

Compounds that have been described as specific inhibitors of COX-2 andare therefore useful in the present invention include, but are notlimited to: parecoxib, CELEBREX® and BEXTRA® or a pharmaceuticallyacceptable salt thereof.

Other examples of angiogenesis inhibitors include, but are not limitedto, endostatin, ukrain, ranpirnase, IM862,5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate,acetyldinanaline,5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin, RP14610, NX31838, sulfatedmannopentaose phosphate,7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalenedisulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone(SU5416).

As used above, “integrin blockers” refers to compounds which selectivelyantagonize, inhibit or counteract binding of a physiological ligand tothe α_(v)β₃ integrin, to compounds which selectively antagonize, inhibitor counteract binding of a physiological ligand to the αvβ5 integrin, tocompounds which antagonize, inhibit or counteract binding of aphysiological ligand to both the α_(v)β₃ integrin and the α_(v)β₅integrin, and to compounds which antagonize, inhibit or counteract theactivity of the particular integrin(s) expressed on capillaryendothelial cells. The term also refers to antagonists of the α_(v)β₆α_(v)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins. The term also refersto antagonists of any combination of α_(v)β₃, α_(v)β₅, α_(v)β₆, α_(v)β₈,α₁β₁, α₂β₁, β₅α₁, α₆β₁ and α₆β₄ integrins.

Some specific examples of tyrosine kinase inhibitors includeN-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide,3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one,17-(allylamino)-17-demethoxygeldanamycin,4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline,N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,BIBX1382,2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one,SH268, genistein, STI571, CEP2563,4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethanesulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571A,N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and EMD121974.

Combinations with compounds other than anti-cancer compounds are alsoencompassed in the instant methods. For example, combinations of theinstantly claimed compounds with PPAR-γ (i.e., PPAR-gamma) agonists andPPAR-δ (i.e., PPAR-delta) agonists are useful in the treatment ofcertain malingnancies. PPAR-γ and PPAR-δ are the nuclear peroxisomeproliferator-activated receptors γ and δ. The expression of PPAR-γ onendothelial cells and its involvement in angiogenesis has been reportedin the literature (see J. Cardiovasc. Pharmacol. 1998; 31:909-913; J.Biol. Chem. 1999; 274:9116-9121; Invest. Opthalmol. Vis. Sci. 2000;41:2309-2317). More recently, PPAR-γ agonists have been shown to inhibitthe angiogenic response to VEGF in vitro; both troglitazone androsiglitazone maleate inhibit the development of retinalneovascularization in mice. (Arch. Ophthamol. 2001; 119:709-717).Examples of PPAR-γ agonists and PPAR-γ/α agonists include, but are notlimited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone,rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate,GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544,NN2344, KRP297, NP0110, DRF4158, NN622, G1262570, PNU182716, DRF552926,2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionicacid (disclosed in U.S. Ser. No. 09/782,856), and2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchromane-2-carboxylicacid (disclosed in U.S. Ser. No. 60/235,708 and 60/244,697).

Another embodiment of the instant invention is the use of the presentlydisclosed compounds in combination with anti-viral agents (such asnucleoside analogs including ganciclovir for the treatment of cancer.See WO 98/04290.

Another embodiment of the instant invention is the use of the presentlydisclosed compounds in combination with gene therapy for the treatmentof cancer. For an overview of genetic strategies to treating cancer seeHall et al (Am J Hum Genet 61:785-789, 1997) and Kufe et al (CancerMedicine, 5th Ed, pp 876-889, BC Decker, Hamilton 2000). Gene therapycan be used to deliver any tumor suppressing gene. Examples of suchgenes include, but are not limited to, p53, which can be delivered viarecombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134,for example), a uPA/uPAR antagonist (“Adenovirus-Mediated Delivery of auPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth andDissemination in Mice,” Gene Therapy, August 1998; 5(8):1105-13), andinterferon gamma (J Immunol 2000; 164:217-222).

The compounds of the instant invention may also be administered incombination with an inhibitor of inherent multidrug resistance (MDR), inparticular MDR associated with high levels of expression of transporterproteins. Such MDR inhibitors include inhibitors of p-glycoprotein(P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833(valspodar).

A compound of the present invention may be employed in conjunction withanti-emetic agents to treat nausea or emesis, including acute, delayed,late-phase, and anticipatory emesis, which may result from the use of acompound of the present invention, alone or with radiation therapy. Forthe prevention or treatment of emesis, a compound of the presentinvention may be used in conjunction with other anti-emetic agents,especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists,such as ondansetron, granisetron, tropisetron, and zatisetron, GABABreceptor agonists, such as baclofen, a corticosteroid such as Decadron(dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten orothers such as disclosed in U.S. Pat. Nos. 2,789,118, 2,990,401,3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, anantidopaminergic, such as the phenothiazines (for exampleprochlorperazine, fluphenazine, thioridazine and mesoridazine),metoclopramide or dronabinol. In an embodiment, an anti-emesis agentselected from a neurokinin-1 receptor antagonist, a 5HT3 receptorantagonist and a corticosteroid is administered as an adjuvant for thetreatment or prevention of emesis that may result upon administration ofthe instant compounds.

Neurokinin-1 receptor antagonists of use in conjunction with thecompounds of the present invention are fully described, for example, inU.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595,5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147; European PatentPublication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430771, 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0512 902, 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681, 0 517589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0545 478, 0 558 156, 0 577 394, 0 585 913, 0 590 152, 0 599 538, 0 610793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0707 006, 0 708 101, 0 709 375, 0 709 376, 0 714 891, 0 723 959, 0 733632 and 0 776 893; PCT International Patent Publication Nos. WO90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151,92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330,93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116,93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181,93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429,94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165,94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767,94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309,95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549,95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129,95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418,95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094,96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304,96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553,97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084,97/19942 and 97/21702; and in British Patent Publication Nos. 2 266 529,2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293169, and 2 302 689. The preparation of such compounds is fully describedin the aforementioned patents and publications, which are incorporatedherein by reference.

In an embodiment, the neurokinin-1 receptor antagonist for use inconjunction with the compounds of the present invention is selectedfrom:2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine,or a pharmaceutically acceptable salt thereof, which is described inU.S. Pat. No. 5,719,147.

A compound of the instant invention may also be administered with anagent useful in the treatment of anemia. Such an anemia treatment agentis, for example, a continuous eythropoiesis receptor activator (such asepoetin alfa).

A compound of the instant invention may also be administered with anagent useful in the treatment of neutropenia. Such a neutropeniatreatment agent is, for example, a hematopoietic growth factor whichregulates the production and function of neutrophils such as a humangranulocyte colony stimulating factor, (G-CSF). Examples of a G-CSFinclude filgrastim.

A compound of the instant invention may also be administered with animmunologic-enhancing drug, such as levamisole, isoprinosine andZadaxin.

A compound of the instant invention may also be useful for treating orpreventing cancer, including bone cancer, in combination withbisphosphonates (understood to include bisphosphonates, diphosphonates,bisphosphonic acids and diphosphonic acids). Examples of bisphosphonatesinclude but are not limited to: etidronate (Didronel), pamidronate(Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate(Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate,EB-1053, minodronate, neridronate, piridronate and tiludronate includingany and all pharmaceutically acceptable salts, derivatives, hydrates andmixtures thereof.

Thus, the scope of the instant invention encompasses the use of theinstantly claimed compounds in combination with a second compoundselected from: other HDAC inhibitors, an estrogen receptor modulator, anandrogen receptor modulator, retinoid receptor modulator, acytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-proteintransferase inhibitor, an HMG-CoA reductase inhibitor, an HIV proteaseinhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor,a PPAR-γ agonist, a PPAR-δ agonist, an anti-viral agent, an inhibitor ofinherent multidrug resistance, an anti-emetic agent, an agent useful inthe treatment of anemia, an agent useful in the treatment ofneutropenia, an immunologic-enhancing drug, an inhibitor of cellproliferation and survival signaling, an agent that interfers with acell cycle checkpoint, an apoptosis inducing agent and a bisphosphonate.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., a cytotoxic agent, etc.), “administration” and its variants areeach understood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician.

The term “treating cancer” or “treatment of cancer” refers toadministration to a mammal afflicted with a cancerous condition andrefers to an effect that alleviates the cancerous condition by killingthe cancerous cells, but also to an effect that results in theinhibition of growth and/or metastasis of the cancer.

In an embodiment, the angiogenesis inhibitor to be used as the secondcompound is selected from a tyrosine kinase inhibitor, an inhibitor ofepidermal-derived growth factor, an inhibitor of fibroblast-derivedgrowth factor, an inhibitor of platelet derived growth factor, an MMP(matrix metalloprotease) inhibitor, an integrin blocker, interferon-α,interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor,carboxyamidotriazole, combretastatin A-4, squalamine,6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin,troponin-1, or an antibody to VEGF. In an embodiment, the estrogenreceptor modulator is tamoxifen or raloxifene.

Also included in the scope of the claims is a method of treating cancerthat comprises administering a therapeutically effective amount of acompound of Formula I in combination with radiation therapy and/or incombination with a compound selected from: other HDAC inhibitors, anestrogen receptor modulator, an androgen receptor modulator, retinoidreceptor modulator, a cytotoxic/cytostatic agent, an antiproliferativeagent, a prenyl-protein transferase inhibitor, an HMG-CoA reductaseinhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor,an angiogenesis inhibitor, a PPAR-γ agonist, a PPAR-δ agonist, ananti-viral agent, an inhibitor of inherent multidrug resistance, ananti-emetic agent, an agent useful in the treatment of anemia, an agentuseful in the treatment of neutropenia, an immunologic-enhancing drug,an inhibitor of cell proliferation and survival signaling, an agent thatinterfers with a cell cycle checkpoint, an apoptosis inducing agent anda bisphosphonate.

And yet another embodiment of the invention is a method of treatingcancer that comprises administering a therapeutically effective amountof a compound of Formula I in combination with paclitaxel ortrastuzumab.

The invention further encompasses a method of treating or preventingcancer that comprises administering a therapeutically effective amountof a compound of Formula I in combination with a COX-2 inhibitor.

The instant invention also includes a pharmaceutical composition usefulfor treating or preventing cancer that comprises a therapeuticallyeffective amount of a compound of Formula I and a compound selectedfrom: other HDAC inhibitors, an estrogen receptor modulator, an androgenreceptor modulator, a retinoid receptor modulator, acytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-proteintransferase inhibitor, an HMG-CoA reductase inhibitor, an HIV proteaseinhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor,a PPAR-γ agonist, a PPAR-δ agonist, an anti-viral agent, an inhibitor ofcell proliferation and survival signaling, an agent that interfers witha cell cycle checkpoint, an apoptosis inducing agent and abisphosphonate.

These and other aspects of the invention will be apparent from theteachings contained herein.

All patents, publications and pending patent applications identified arehereby incorporated by reference.

Abbreviations used in the description of the chemistry and in theExamples that follow are:

AcOH (acetic acid); BuLi (n-butyl lithium); BSA (bovine serum albumin);DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DCE (1,2-dichloroethane);DIPEA (diisopropylethylamine); DCM (dichloromethane); DME (ethyleneglycol dimethyl ether); DMEM (Dulbecco's Modified Eagle Medium); DMF(dimethylformamide); DMSO (dimethyl sulfoxide); DPPA(diphenylphosphorazide); DTT (dithiothreitol); EDC and EDCI(N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide); EDC.HCl(1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride); EDTA(ethylenediaminetetraacetic acid); EGTA (Ethyleneglycotetraacetic acid);em (emission); Eq. (equivalent); ES (electrospray); EtOAc (ethylacetate); EtOH (ethanol); ex (exitation); FACS (fluorescence activatedcell sorting); FITC (Fluorescein isothiocyanate); Hepes((N-(2-Hydroxyethyl)piperazine)-N′-(2-ethanesulfonic acid)); HOBt(1-hydroxybenzotriazole); HPLC (high performance liquid chromatography);IPTG (Isopropyl-beta-D-thiogalactopyranoside); LEP (Lysyl EndPeptidase); Lys C (Lysyl C endoprotease); MeCN (acetonitrile); MeOH(methanol); MS (mass spectrometry); NMR (nuclear magnetic resonance);NP40 (Nonidet P40); PBS (Phosphate buffered saline); PMSF(phenylmethylsulphonyl fluoride); ^(i)PrOH (iso-propanol), PTSA(p-Toluenesulphonic acid); PyBop(1H-1,2,3-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphoniumhexafluorophosphate); RP (reverse phase); RT (room temperature); SCX(Varian or Isolute cation exchange resin); SiO₂ (silica gel); TEA(triethyl amine); THF (tetrahydrofuran); TFA (trifluoroacteic acid);Tris-HCl (Tris Hydroxymethylaminoethane); and TSA (Trichostatin A).

Further abbreviations include:

App (Apparent); PS-BEMP(2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine);Py (pyridine); sat. aq (saturated aqueous); SEM-Ci([2-(chloromethoxy)ethyl](trimethyl)silane); TBAF (Tetrabutylammoniumfluoride); TBTU (2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate); TFAA (Trifluoroacetic anhydride); and TsCl (paratoluene sulfonyl chloride). A further abbreviation is BOM(benzyloxymethyl).

Compounds of formula I may be prepared by reacting a compound of formulaIV with a compound of formula V:

wherein D, R¹, R², R³, R⁴, R⁵, R⁶, R⁸, X, Het, p, q and t are as definedfor formula I and L′ is a leaving group such as hydroxy or chlorine.When L¹ is a leaving group such as chlorine, the reaction is generallycarried out in the presence of a base such as Et₃N and a solvent such asDMF or DCM at about room temperature. When L¹ is a leaving group such ashydroxy, a coupling agent such as EDC.HCl and a base such as Et₃N mayalso be added. Further additives such as HOBt and DIPEA may also bepresent.

Protecting groups such as SEM on the Het ring and dioxane at thecarbonyl position of the compounds of formula IV may be present duringthe reaction. The compounds can subsequently be deprotected usingstandard methods, such as adding TBAF in a solvent such as THF atreflux, or adding DCM and TFA or HCl(aq) in a solvent such as THF atabout room temperature.

Compounds of formula IV wherein Het is imidazole may be prepared byreacting a compound of formula VI:

wherein D, R¹, R², R⁴ and q are as defined above and P is a protectinggroup such as Boc with a cyclisation agent such as ammonium acetate,generally in a solvent such as xylene at about 150° C.

Compounds of formula VI can be prepared by reacting a compound offormula VII with a compound of formula VIII:

wherein D, R¹, R², R⁴, q and P are as defined above and L² is a leavinggroup such as halogen, particularly bromine, generally in the presenceof a base such as cesium carbonate in a solvent such as DMF at roomtemperature.

Compounds of formula IV in which R⁴ is hydrogen may alternatively beprepared by reacting a compound of formula IX:

wherein D, R¹, R², Het and q are as defined above with an azide reagentsuch as diphenylphosphorazide, generally in the presence of a base suchas DBU and in a solvent such as toluene. The resulting azide may then behydrogenated to produce the compound of formula IV wherein R⁴ ishydrogen. For example, the reaction can be carried out firstly underhydrogen and then nitrogen atmosphere, in a solvent such as EtOAc and inthe presence of a catalyst such as Pd on carbon. Alternatively, theresulting azide may be reacted with organophosphine such as PPh₃ and insolvents such as THF and water at about room temperature. Protectinggroups such as SEM on the Het ring and dioxane at the carbonyl positionof the compounds of formula IX may be present during the reaction.

Compounds of formula IX may be prepared by reacting a compound offormula X with a compound of formula XI:

wherein D, R¹, R², Het and q are as defined above and L³ is a halogenatom such as bromine, generally in a solvent such as THF.

Compounds of formula IV may alternatively be prepared by reacting acompound of formula XII:

wherein D, R¹, R², R⁴, Het, q and P are as defined above with anoxidising agent such as Dess-Martin periodinane, generally in a solventsuch as DCM at about room temperature.

Compounds of formula XII in which Het is a triazole ring may be preparedby reacting a compound of formula XIII with a compound of formula XIV:

wherein D, R¹, R², R⁴, q and P are as defined above and R′ is C₁₋₆alkyl,such as methyl, generally in a solvent such as toluene at about roomtemperature.

Compounds of formula XIII can be prepared by reacting a compound offormula XV:

wherein R², R⁴, q and P are as defined above and R″ is C₁₋₆alkyl, suchas methyl, with hydrazine hydrate, generally in the presence of analcoholic solvent such as isopropanol at about 80° C.

Compounds of formula XV can be prepared by reacting a compound offormula VII with a reducing agent such as BH₃Me₂S, generally in asolvent such as THF at about 0° C.

Compounds of formula IV wherein Het is 1,3,4-oxadiazole can be preparedby reacting a compound of formula XVI:

wherein D, R¹, R², R⁴, q and P are as defined above with cyclisationagents such as PS-BEMP and TsCl, generally in a solvent such as THF atabout 65° C.

Compounds of formula XVI can be prepared by reacting a compound offormula XVII:

wherein D, R¹, R², R⁴, q and P are as defined above with an oxidisingagent such as Dess-Martin periodinane, generally in a solvent such asDCM at about room temperature.

Compounds of formula XVII can be prepared by reacting a compound offormula XIII with a formula of XVIII:R¹-D-CO₂H  (XVIII)wherein D and R¹ are as defined above, generally in the presence ofcoupling agents such as HOBt and EDC.HCl in a solvent such as DCM atabout room temperature.

Compounds of formula IV wherein Het is oxazole can be prepared byreacting a compound of formula XIX:

wherein D, R¹, R², R⁴, q and P are as defined above with cyclisationagents such as hexachloroethane (C₂Cl₆) and triphenylphosphine (PPh₃),generally in the presence of a base such as Et₃N and in a solvent suchas DCM at about room temperature.

Compounds of formula XIX can be prepared by reacting a compound offormula VII with a compound of formula XX:

wherein D and R¹ are as defined above. The reaction is generally carriedout in the presence of coupling agents such as HOBt and EDC.HCl, in abase such as DIPEA and a solvent such as DMF.

Compounds of formula XX can be prepared by hydrogenation of thecorresponding azido of formula XXI:

wherein D and R¹ are as defined above. The reaction is generally carriedout in an acid such as HCl, in the presence of a catalyst such as Pd oncarbon and in a solvent such as methanol at about room temperature.

Compounds of formula XXI can be prepared by reacting a compound offormula VIII with an azide source such as NaN₃, generally in a solventsuch as acetone at about room temperature.

Compounds of formula IX can alternatively be prepared by reacting acompound of formula XXII with an organometallic reagent such as BuLi tofacilitate a halogen-lithium exchange, followed by quenching with acompound of formula XXIII:

wherein D, R¹, R², q and Het are as defined above and L² is a leavinggroup such as halogen, particularly bromine. The reaction is generallycarried out in a solvent such as THF at about −78° C. A protecting groupsuch as SEM may be present as described previously.

Compounds of formula XXII can be prepared by reacting a compound offormula XXIV with a compound of formula XXV;

wherein D, R¹ and L² are independently as defined above. The reaction isgenerally carried out in a solvent such as toluene and in the presenceof a catalyst such as Pd(PPh₃)₄ at reflux.

Compounds of formula XXIII can be prepared by reacting a compound offormula XXVI:

wherein R² and q are as defined above and R^(x) and R^(y) areindependently C₁₋₆alkyl groups such as methyl, with a reducing agentsuch as LiAlH₄, generally in a solvent such as THF at about −78° C.

Compounds of formula IX can alternatively be formed by reacting acompound of formula XXVII with an organometallic reagent derived fromtreating a compound of formula XXVIII with a reagent such as tert-BuLi:

wherein D, R¹, R², q, Het, R^(x), R^(y) and L² are as defined above. Thereaction is generally carried out in a solvent such as THF and pentaneat about −78° C. The ketone can subsequently be converted to therequired alcohol in the presence of a reducing agent such as NaBH₄ andin a solvent such as ethanol at about room temperature.

Compounds of formula IV wherein R⁴ is hydrogen can alternatively beprepared by reacting an organometallic reagent derived from a compoundof formula XXII with a compound of formula XXIX:

wherein R² and q are as defined above and P¹ is a chiral auxiliary suchas tert-butanesulfine. The reaction is generally carried out in asolvent such as THF, at about −78° C. The P¹ group such astert-butanesulfine can subsequently be removed under acidic conditions,such as HCl in a solvent such as methanol at about room temperature.

Compounds of formula XXIX can be prepared by reacting a compound offormula XXIII with a compound of formula XXX:P¹—NH₂  (XXX)wherein P¹ is as defined above, generally in the presence of a catalystsuch as copper sulfate (CuSO₄), in a solvent such as DCM at about roomtemperature.

Compounds of formula XVI can alternatively be prepared by reacting acompound of formula VII with a compound of formula XXXI:

wherein D and R¹ are as defined above. The reaction is generally carriedout in the presence of coupling agents such as EDC.HCl and HOBt, in asolvent such as DMF at room temperature.

Compounds of formula XII wherein Het is oxadiazole can alternatively beprepared by reacting a compound of formula XVIII with a compound offormula XXXII:

wherein R², R⁴, P and q are as defined above. The reaction is generallycarried out in the presence of coupling agents such as TBTU and HOBt, ina base such as DIPEA and in a solvent such as DMF at about roomtemperature and then heated at about 110° C.

Compounds of formula XXXII can be prepared by reacting a compound offormula XXXIII:

wherein R², R⁴, P and q are as defined above, with a hydroxyaminoreagent such as NH₂OH.HCl, generally in a solvent such as methanol andin the presence of a base such as KOH at reflux.

Compounds of formula XXXIII can be prepared by reacting a compound offormula XXXIV:

wherein R², R⁴, P and q are as defined above with a dehydrating agentsuch as TFAA, generally in the presence of a base such as Et₃N and in asolvent such as DCM at about 0° C. A further reducing agent such asNaBH₄ in a solvent such as methanol can subsequently be added to reducethe carbonyl group at the R² position.

Compounds of formula XXXIV can be prepared by reacting a compound offormula VII with an amino source such as ammonium bicarbonate, generallyin the presence of pyridine and Boc₂O, in a solvent such as dioxane atabout room temperature.

Compounds of formula IV wherein Het is a 1,2,4-oxadiazol-5-yl can beprepared by reacting a compound of formula VII with a compound offormula XXXV:

wherein D and R¹ are as defined above, generally in the presence ofcoupling reagents such as TBTU and HOBt, in a base such as DIPEA and ina solvent such as DMF at about room temperature and then at atemperature of about 110° C.

Alternatively, compounds of formula I wherein R² is methyl can beprepared by reacting a compound of formula XXXVI:

wherein D, R¹, R³, R⁴, R⁵, R⁶, R⁸, X, p, q, t and Het are as definedabove with an oxidising agent, such as oxygen gas and CuCl, in thepresence of a catalyst such as PdCl₂ and in a solvent such as DMF.

Compounds of formula XXXVI can be prepared by reacting a compound offormula V with a compound of formula XXXVII:

wherein D, R¹, R⁴, Het and q are as defined above, generally undercoupling conditions as described previously.

Compounds of formula XXXVII wherein R⁴ is hydrogen can be prepared byreacting a compound of formula XXXVIII:

wherein D, R¹, Het and q are as defined above with an organophosphinesuch as PPh₃ and solvents such as THF and water at about roomtemperature.

Compounds of formula XXXVIII can be prepared by reacting a compound offormula XXXIX:

wherein D, R¹, Het and q are as defined above with an azide reagent suchas diphenylphosphorazide, generally in the presence of a base such asDBU and in a solvent such as toluene at about 50° C.

Compounds of formula XXXIX can be prepared by reacting a compound offormula X with a compound of formula XL:

wherein L³ and q are as defined above, generally in a solvent such asTHF at about 0° C. and under an argon atmosphere.

Compounds of formula I may alternatively be prepared by reacting acompound of formula XXV with a compound of formula XLI:

wherein R², R³, R⁴, R⁵, R⁶, R⁸, X, Het, p, q, t and L² are as definedabove. The reaction is generally carried out in a solvent such as n-BuOHand in the presence of catalysts such as Pd(OAc)₂, K₃PO₄ anddicyclohexly-(2′,6′-dimethoxybiphenyl-2-yl)phospene, at about 90° C.

Protecting groups such as SEM on the Het ring may be present during thereaction, which can subsequently be removed under standard conditionsdescribed above.

Compounds of formula XXXI can be prepared by reacting a compound offormula XLII with hydrazine monohydrate:

wherein D and R¹ are as defined above and L⁴ is an appropriate leavinggroup such as methoxy. The reaction is generally carried out in asolvent such a i-PrOH at about 80° C.

Compounds of formula IX may alternatively be prepared by reacting acompound of formula X with an organometallic reagent derived fromreacting a compound of formula XXVIII with a reagent such as tert-BuLi.The reaction is generally carried out in a solvent such as Et₂O at aboutroom temperature.

The Het group may be protected as described previously.

Alternatively, compounds of formula I when X is C, t is 1 and R⁵ ishydrogen can be prepared by reacting a compound of formula IV with acompound of formula XLIII:OCN—(CR⁶R⁸)_(p)—R³  (XLIII)wherein R³, R⁶, R⁸ and p are as defined above. The reaction is generallycarried out in the presence of a base such as DIPEA, in a solvent suchas DCM at about room temperature.

Where the synthesis of intermediates and starting materials is notdescribed, these compounds are commercially available or can be madefrom commercially available compounds by standard methods or byextension of the Examples herein.

Compounds of formula I may be converted to other compounds of formula Iby known methods or by methods described in the Examples.

Thus, compounds of formula I wherein R² is hydroxy can be converted tocompounds of formula I wherein R² is N(R^(b))₂ by reacting withHN(R^(b))₂, generally in the presence of a coupling agent such as EDCIand DMAP and in a solvent such as DCM at about room temperature. HATUmay also be used, generally in a solvent such as 1,4-dioxane. Couplingagents such as ED.HCl and HOBt, a base such as DIPEA and a solvent suchas DMF at about room temperature may also be used.

Compounds of formula I wherein R² is hydroxy can be converted intocompounds of formula I wherein R² is perfluoroalkyl by reacting with aperfluoroalkylacetic anhydride such as TFAA, generally in the presenceof a base such as pyridine and a solvent such as DCM at about 0° C.

Compounds of formula I wherein R² is N(R^(b))₂ may be converted tocompounds wherein R² is C₁₋₆alkylS(O)_(w)R^(g) by reacting with anorganometallic reagent derived from treating a compound of formulaH—C₁₋₆alkylS(O)_(w)R^(g) with a reagent such as n-BuLi, generally in asolvent such as THF at a temperature from about −78° C. to roomtemperature.

Compounds of formula I wherein R² is N(R^(b))₂ can be converted tocompounds wherein other groups are present at R² by reacting with anappropriate organometallic reagent such as an organolithium or grignardreagent derived from the required R² group. The reaction is generallycarried out in a solvent such as THF and at a temperature from about−78° C. to room temperature Compounds of formula IV wherein R² ishydrogen can be converted to compounds wherein R² is other than hydrogenby reacting with an organometallic reagent derived from treating acompound of formula XLIV with a reagent such as n-BuLi:R²-L³  (XLIV)wherein R² and L³ are as defined above. The reaction is generallycarried out in the presence of a solvent such as THF at about 0° C. toroom temperature. The resulting alcohol there formed can then beoxidized to compounds of formula IV using reagents such as Dess-Martinreagent. If appropriate, functionality elsewhere in the molecule can beprotecting with the appropriate protecting groups as describedpreviously.

During any of the synthetic sequences described herein it may benecessary and/or desirable to protect sensitive or reactive groups onany of the molecules concerned. This may be achieved by means ofconventional protecting groups, such as those described in ProtectingGroups in Organic Synthesis, 3rd Edition, Greene, T. W. and Wuts, P. G.M.; Wiley Interscience, 1999 and Kocienski, P. J. Protecting Groups,Thieme, 1994. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art. For example, when theBoC protecting group is present, it may be removed by the addition ofsolvents such as TFA and DCM. The compound may also be hydrogenatedusing standard methods, such as treating with a catalyst such ad Pd/C,in a solvent such as methanol in a hydrogen atmosphere.

As described previously the Het group may be protected by protectinggroups such as SEM during the synthesis of the compounds of formula I,which can subsequently be removed under standard conditions as describedabove.

Further examples of protecting groups on the Het ring includetert-butyl(dimethyl)silylmethyl and BOM. The BOM group may subsequentlybe removed using standard methods, for example by the addition of areagent such as BBr₃ and a solvent such as toluene at about roomtemperature.

Compounds of this invention can be prepared as described in Scheme 1from a suitably elaborated alkyl chain functionalised in the α-positionwith an amino derivative. These derivatives can be prepared by thoseskilled in the art and methods to synthesise such heterocycles aredescribed in Alan Katritzky, Comprehensive Heterocyclic Chemistry,(Pergamon Press, New York, 1984) and Comprehensive Heterocylic ChemistryII, (Pergamon Press, New York, 1996) amongst other texts. The free aminogroup can be coupled with an acid derivative to from amides, methods forcoupling carboxylic acids (and acid derivatives) with amines to formcarboxamides are well known in the art. Suitable methods are described,for example, in Jerry March, Advanced Organic Chemistry, 3rd edition,John Wiley & Sons, 1985, pp. 370-376. Likewise reaction with a sulfonylchloride in the presence of base gives the corresponding sulfonamide,see Jerry March, Advanced Organic Chemistry, 4th edition, John Wiley &Sons, 1992, pp. 496-499. In a similar manner, reaction of the amine witha sulfamoyl chloride gives the corresponding sulfamide.

A route to pendant imidazoles is shown in Scheme 2 from the keyprotected amino ester (these amino acid derivatives can be prepared bythose skilled in the art using standard chemistry, such as described inWilliams, R. M. Synthesis of Optically Active α-Amino Acids, PergamonPress, 1989). These acids can be alkylated with a halomethyl ketone inthe presence of base, for example Cs₂CO₃, and the resulting ester istreated with an excess of ammonium acetate and heated at 150° C. toyield the desired imidazole, such conditions are described in Bioorg.Med. Chem. Lett. 1996, 6, 1601, Tetrahedron 1996, 52, 10131 and J. Am.Chem. Soc. 1981, 103, 3446. Removal of the protecting group enablesfurther functionalisation. Examples include: amide formation by reactionof an acid in the presence of coupling reagent; sulfonylation byreaction of a sulfonyl chloride in the presence of base; andsulfamoylation by reaction with a sulfamoyl chloride and base.

Compounds of this invention can be prepared as described in Scheme 3from a suitable heterocyclic aldehyde (commercially available or readilysynthesised by oxidation of the corresponding alcohol) by reacting witha Grignard reagent, itself prepared under standard conditions from thecorresponding alkyl bromide with magnesium turnings in refluxing THF.The resulting secondary alcohol thereby obtained can be reacted withdiphenylphosphorazide and DBU using the conditions of Thompson et al.(J. Org. Chem. 1993, 58, 5886-8) to yield the azide. Hydrogenation atatmospheric pressure using palladium on carbon as catalyst gives racemicamine which can then be coupled with carboxylic acids, sulfonylchlorides and sulfamyl chloride. Final deprotection with mineral acidliberates the corresponding ketone.

A modification of the route to the pendant imidazoles is shown in Scheme4 whereby the alkylated acid is treated with a mixture of ammoniumacetate and an alkyl ammonium acetate at 150° C. in xylene to give amixture of products including the desired alkylated imidazole. Thecompounds then can be manipulated as described previously to give thedesired inhibitors

A route to give triazoles is shown in Scheme 5 where the amino acidbearing a ketone is first reduced, for instance with BH₃.Me₂S complex,to the alcohol and then the ester group converted into the hydrazide byheating in the presence of hydrazine hydrate in an alcoholic solvent.This hydrazine is then reacted with an imino ether, first at RT and thenat 110° C. to yield the desired heterocycle. Finally oxidation of thealcohol back to the corresponding ketone yields an intermediate whichcan be converted into the required inhibitors as described previously.

A method to prepare further analogues is illustrated in Scheme 6 wherebyalkylation of a lithiated Schollkopf derivative with a suitablyfunctionalised alkyl iodide gives after mild acid hydrolysis a chiralα-amino ester (see U. Schollkopf et al. Synthesis 1982, 866).Saponification yields to the chiral α-amino acid. This acid can betransformed into the requisite imidazole as already outlined, firstly byalkylation with an α-bromoketone and then by treatment with ammoniumacetate in xylene at 150° C. Deprotection, for instance with a mixtureof TFA in DCM liberates the ammonium salt, which can be coupled to givethe desired inhibitors

The carboxylic acid can be further functionalised by coupling to avariety of N(R^(b))₂ groups to yield amides and hydroxamic acids asdesired inhibitors, for instance, using EDC as coupling reagent, asillustrated in Scheme 7.

A synthetic route to the preparation of 1,3,4-oxadiazoles is shown inscheme 8 where a hydrazide is readily coupled with a second carboxylicacids and then cyclised under dehydrative conditions to form the desiredheterocyclic ring. Suitable conditions include the use of tosyl chlorideand polymer supported BEMP as described by Brain et al. Synlett 2001, 3,382-384. Subsequently, the protecting group can be removed from thenitrogen atom and the required inhibitors can be synthesised aspreviously described.

Isomeric 1,2,4-oxadiazoles can be prepared as described in scheme 9. Theamino acid can be coupled to make the primary amide, which in turn canbe dehydrated to the nitrile using reagents such as trifluoroaceticanhydride and a base. In certain cases, a reductive step is required toensure functional group compatibility with an oxidative step later inthe synthetic sequence. Formation of the aldoxime can be achieved withhydroxylamine.HCl in the presence of potassium hydroxide. Thecyclisation to the oxadiazole can be accomplished by coupling with acarboxylic acid using TBTU as coupling reagent and then heating thereaction at 111° C. to accomplish the cyclisation as described by Poulinet al. Tetrahedron Letters 2001, 42, 1495-8. Alternatively, tosynthesise the isomeric heterocycle, the coupling partners can beinverted, and the reaction of the α-amino acid with the aldoxime derivedfrom the heterocycle inverts the substitution pattern.

An alternative procedure, in this case for the preparation of oxazoles,is shown in scheme 10 where an α-aminoketone is coupled with acarboxylic acid, the resulting amide there formed can then be cyclisedagain under dehydrative conditions to yield the desired heterocycle. Onemethod for performing the cyclisation is to use hexachloroethane andtriphenylphosphine as described by Nicolaou et al. J. Am. Chem. Soc.2004, 126, 10162-10173.

An alternative procedure to that shown in scheme 3 to introduce otherheterocycles is outlined in scheme 11. For instance, a suitableelaborated Weinreb amide could be reacted with an organometallic speciesto yield the corresponding ketone. Suitable organometallic reagentsinclude organolithium species, which are readily available fromhalogen-lithium exchange or alternatively from deprotonatingheterocycles with strong base, for instance see: L. Brandsma and H.Verkruijsse, Preparative Polar Organometallic Chemistry 1,Springer-Verlag. The key ketone can also be prepared by the addition ofa alkyl-lithium, available from halogen-lithium exchange of the alkyliodide/bromide with tert-BuLi (as described in J. Am. Chem. Soc. 1990,55, 5404 and 5406), to an heterocyclic Weinreb amide. These ketones canreadily be converted to the required alcohols using reducing agents suchas sodium borohydride.

The alcohols can also be made directly by the above methods but using analdehyde in place of the Weinreb amide and thereby eliminating thereduction step.

An alternative to this strategy involves the use of a terminal alkene asa masked methyl ketone group, the latter can readily be unmasked byWacker oxidation as show in scheme 12. The alkene is readily introducedinto the inhibitors through generation of the Grignard reagent fromω-haloalk-1-enes and their addition to aldehydes. Conversion of thebenzylic alcohols to the corresponding amines is accomplished asdescribed above using DPPA and DBU to form the azide and a Staudigerreaction to reduce the azide to the requisite amine. Afterfunctionalisation of the amine, the alkene can readily be converted tothe ketone using oxygen and CuCl and catalytic PdCl₂ as described inSynthesis 1984, 369-384.

A variant of the above procedure is to adopt Ellman chemistry to enablethe key amine to be produced in a stereospecific way as shown in scheme13. Condensation of an aldehyde with (R)-tert-butylsulfinamide resultsin the formation of the N—(R)-tert-butylsulfinimine. Addition of anorganometallic reagent to this imine can be achieved in a highlystereospecific manner as described in: Tetrahedron 1999, 55, 8883-8904;J. Org. Chem. 1999, 64, 1278-84 and J. Comb. Chem. 2003, 5, 590-6, andthe diastereomers can be separated as necessary. Hydrolysis of thechiral auxiliary with acidic methanol yields the key chiral aminesuitable for further functionalisation.

Perfluoroalkyl ketones can be prepared as described in scheme 14 wherebythe corresponding carboxylic acid is deprotonated and then thecorresponding anion is reacted with perfluoroalkylacetic anhydride, suchas TFAA, in the presences of a base such as pyridine to yield thefluoroalkyl ketone as described in Tetrahedron Letters, 1992, 33,1285-8.

In some circumstances the desired inhibitors can be converted into otheranalogues by simple functional group manipulations known to thoseskilled in the art. For instance, carboxylic acids contained in thevarious R^(x) groups can be cleaved and coupled to introduce amidegroups. Likewise protected amines in the R^(x) groups can be deprotectedand functionalised with reactions such as coupling to carboxylic acidderivatives or by reductive amination reactions as shown in Scheme 15.

A modification of Scheme 13 is shown in Scheme 16 whereby2,5-dibromoimidazole is protected and then lithiated, by bromine-lithiumexchange with BuLi, and added to the tert-butylsulfinimine of the alkylchain to give a mixture of diastereomers which can be separated readilyby chromatography. Hydrolysis of the chiral auxiliary is readilyachieved in acidic media and coupling introduces one of the cappinggroups. Cross-coupling reaction, for instance Suzuki reaction with aboronic acid under palladium catalysis, introduces the R¹-D-group andfinal deprotection readily liberates the desired inhibitors.

A further modification is shown in Scheme 17 whereby the bromide can becross coupled in a Stille reaction with an 1-(1-alkoxyalkenyl)stannanein the presence of palladium(0) catalysis and then hydrolysed to yieldcompounds with a ketone moiety present in the R¹-D-group. Alternatively,if the bromide is cross-coupled in a Suzuki reaction with an alkenylboronic acid the resulting product with a double bond present in theinhibitor can be subjected to a hydrogenation reaction to yieldderivatives with alkyl groups at D.

Further modification in the nature of the R¹-D-substitutent can be madeby carrying through a protected hydroxylmethyl group through thesynthetic sequence as shown in Scheme 18. Lithiation on the 2-positionof the imidazole and quenching on DMF introduces a aldehyde group on theimidazole, and this in turn can be reacted with a functionalisedorganolithium reagent, comprising of the side chain of the inhibitors,to build up the core of the desired molecules. Conversion of theresulting secondary alcohol into the corresponding azide and hydrolysiswith PPh₃ in a Staudinger reaction liberates an amine which can becoupled to introduce one of the capping groups. This key building blockcan then be elaborated into a number of different classes of inhibitorsas shown above. For instance: deprotection affords a hydroxylmethylR¹-D-group; whereas removal of the silicon protecting groups andoxidation gives a key aldehyde which in turn can be functionalised byreductive aminations to introduce amines on the R¹-D-sidechain,alternatively the aldehyde can easily be homologated by reactions suchas Wittig olefinations to form unsaturated compounds which can behydrogenated to their saturated counterparts.

An alternative procedure to scheme 8 is shown above in scheme 19, wherea hydrazide bearing the desired R¹-D-group is coupled with an activatedamino-acid derivative. Suitable pre-activation strategies includetreatment of the amino acid component with EDCI and HOBt for 10 minutesprior to the addition of the hydrazide. The resulting compound can thenbe readily cyclised under dehydrative conditions, such as the use oftosyl chloride and polymer supported BEMP. Functional groupmanipulations yield the desired inhibitors.

A procedure to modify the nature of the R²-group is shown in Scheme 20whereby a Weinreb amide is treated with an organometallic reagent,typically an organolithium reagent or a Grignard reagent, to give riseto a series of alkyl ketones and functionalised alkyl ketones. Aparticular example is when the organolithium is generated fromchloroiodomethane. In this case, the intermediate thereby formed can betreated with potassium acetate to yield the acetoxymethylketone whichupon basic cleavage yields the hydroxymethyl ketone.

A variant of these procedures (not shown) is to use an aldehyde in placeof the Weinreb amide. In this case after the addition of theorganometallic reagent an oxidation step is required to give thecorresponding ketone, this can be achieved with Dess-Martin reagent.

A modification of Scheme 6 is shown above in Scheme 21 whereby throughcareful choice of the protecting groups, such as the use of a Cbz-groupas the amino protecting group, the tert-butyl ester can be cleavedwithout touching the amino protecting group. This allows the nature ofthe R²-group to be varied and then at a final stage the amino protectinggroup can be removed and a variety of the capping groups introduced.

The exemplified compounds described herein were tested by the assaysdescribed below and were found to have an IC₅₀ value of less than 10 μM.

HDAC1 and NE Assays

Assay Description:

The HDAC_NE and HDAC1 assays are used to quantify the histonedeacetylase (HDAC) activity. The assay is performed in 96 wellmicrotiter plates by pre-incubating serial dilutions of compounds with afixed concentration of HeLa nuclear extract or purified HDAC1 and thenadding an acetylated lysine-containing substrate/developer thatfluoresces upon deacetylation. The deacetylase reaction is performed at37° C. for 60 min, terminated by addition of the developer solution, andthen fluorescence (ex 360 nM, em 460 nM) is measured using a platereader.

HDAC Substrate Buffer System

Reagents of the HDAC Fluorescent Activity Assay are purchased fromBioMol Research Laboratories (Plymouth Meeting, Pa.) and feature theFluor-de-Lys™ Substrate/Developer System. The reagents include theproprietary fluorescent substrate as a 50 mM stock solution (KI-104),and the Developer Concentrate (KI-105). Deacetylation of the lysineresidue of the Fluor-de-Lys substrate is quantified by measuring thefluorescence (ex 360 nM, em 460 nM) after addition of the proprietaryDeveloper.

Working Reagents:

TSA Stock: TSA is provided as a 10 mM stock solution in 100%dimethylsulfoxide (DMSO).

Assay Buffer: 25 mM Tris/HCl pH8, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl2,0.1 mg/ml BSA

Diluted Substrate Solution: The commercial 50 mM Fluor-de-Lys substrate(KI-104) is diluted to 150 uM with HDAC Assay Buffer prior to each use.The final concentration in the assay is 30 uM.

Diluted Developer Solution: The commercial 20X Developer Concentrate(KI-105) is diluted 1:167 into HDAC Assay Buffer. 2 uM [final] TSA tothis solution increases its ability to stop the reaction.

HDAC_NE Working Solution: The HeLa nuclear extract is diluted in assaybuffer prior to each use from a fresh aliquot. The final concentrationin the assay is 20 ug/ml.

HDAC1 Working Solution: The HDAC1 enzyme is diluted in assay bufferprior to each use from a fresh aliquot of enzyme. The finalconcentration in the assay is 1-2 nM.

Compounds: Test compounds should be prepared as a 10×5% DMSO solution inassay buffer. The final DMSO concentration in the reaction is 0.5%.

Experimental Design:

The reaction is performed in 96-well microplate in a final volume of 50ul/well, as following:

-   -   Add 5 ul of DMSO/compound solution    -   Add 35 ul of HeLa NE or HDAC1 in assay buffer (or 35 ul assay        buffer in the negative controls)    -   Incubate 10′ at room temperature    -   Start the reaction by adding 10 ul of the 150 uM Substrate        Solution    -   Incubate 1 h at 37° C.    -   Stop by adding 50 ul of Developer/4 uM TSA solution    -   Incubate 10 min at room temperature    -   Measure the fluorescence at Ex.360 nM and Em.460 nM        Protocol for Nuclei Extraction from HeLa Cells (Adherent or in        Suspension)

For a protocol on Nuclei extraction from HeLa S3 cells (adherent or insuspension) refer to Nare et al. 1999 Anal. Biochem., 267: 390-396.

Nuclei preparation for adherent HeLa S3 cells (0.5-1×109 cells) is asfollows: wash cells twice with 1×PBS, scrape cells into 1×PBS, washplates with 1×PBS, pool and spin cells at 800×g 10 minutes at 4° C.,wash cell pellets with 1×PBS (count cells), spin cells at 800×g 10minutes at 4° C., freeze cell pellets in liquid nitrogen and store −80°C.

Nuclei preparation for HeLa S3 cells in suspension (0.5-1×109 cells) isas follows: collect cells by centrifugation at 800×g 10 minutes at 4°C., wash cell pellets with 1×PBS, spin cells at 800×g 10 minutes at 4°C., repeat wash step twice (count cells), freeze cell pellet in liquidnitrogen and store at −80° C.

Resuspend cell pellets in lysis buffer (5 ml/1×108 cells; buffercontains: 0.25M sucrose, 0.45% NP40, 10 mM Tris-HCl (7.5), 10 mM NaCl, 5mM MgCl₂, 0.1 mM EGTA, 0.5 mM PMSF, COMPLETE protease inhibitor mix),vortex 10 sec and leave on ice for 15 minutes, spin through cushion (25ml of lysate/5 ml cushion; cushion contains: 30% sucrose, 10 mM Tris-HCl(7.5), 10 mM NaCl, 3 mM MgCl₂), spin through cushion at 1,300×g 10minutes at 4° C., remove super/cushion, resuspend in lysis buffer asabove and re-spin through cushion as above, remove super/cushion.

For nuclear extraction, resuspend nuclear pellets in nuclei extractionbuffer (13.5 ml/5 ml nuclear pellet; nuclei extraction buffer contains:50 mM Hepes pH 7.4, sonicate into suspension on ice (1 min, outputcontrol between 4 and 5), leave on ice 30 min., centrifuge 100,000×g for1 hr at 4° C., keep super on ice, repeat sonication/ice/centrifuge stepstwo more times, pool three supernatants and dialyze in 50 mM Hepes pH7.4/10% glycerol and Snap-freeze suitable aliquots in liquid nitrogenand store −80° C.

Extraction and Purification Protocol for Flag-Tagged HDAC1 Expressed inHeLa Cells

HeLa cells transiently transfected with pCDNA3-HDAC1-FLAG are grown to80% confluence on 10 cm culture dishes in DMEM, 10% Fetal bovine serumsupplemented with antibiotics and glutamine. Cells are washed with 10 mlcold PBS and scraped into 2 ml of PBS. Cells are centrifuged for 5minutes at 800×g at 4° C., washed with 30 ml PBS and resuspended in 10ml PBS, counted, re-centrifuged and frozen at −80° C.

The frozen cell pellet is re-suspended in 1 ml of hypotonic lysis buffer(LB: 20 mM Hepes pH7.9, 0.25 mM EDTA, 10% glycerol) containing COMPLETEprotease inhibitor and incubated on ice for 15 minutes, followed byhomogenization on a 2-ml DounceB homogenizer (25 strokes). 150 mM KCland 0.5% NP-40 are added to the homogenate and the solution is sonicatedtwice for 30 seconds (output5/6, duty cycle 90) and incubated for 1 hourat 4° C. After a 30 minutes centrifugation at 12000 rpm and 4° C. thesupernatant (soluble extract) is collected and protein concentration isdetermined using the BIORAD assay.

Anti-FLAG M2 affinity resin (Sigma) is washed three times with TBS andtwice with LB. 10 μl of the LB-washed resin/mg of protein (2-3 ug ofFlagged-HDAC1) are added to the soluble extract (1 mL) and incubatedovernight at 4° C. with gentle mixing. The resin is then collected bycentrifugation, washed once with LB, twice with LB+0.1% NP40 and twicewith elution buffer (50 mM Hepes pH 7.4, 5% glycerol, 100 mM KCl, 0.01%Triton X-100).

The affinity-purified HDAC is eluted from the resin by addition of a10-fold excess (with respect to the resin) of elution buffer containing100 μg/ml 3×FLAG peptide (SIGMA). The concentration of purified HDAC isdetermined by Western blot analysis.

Other assays are known in the literature and can be readily performed bythose skilled in the art.

The following Examples illustrate the present invention.

Example 11-Methyl-3-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}carbonyl)piperidiniumbis(trifluoroacetate) (A4) Step 1:(2S)-2-[(tert-Butoxycarbonyl)amino]-8-oxononanoic acid (A1)

(2S)-2-[(tert-Butoxycarbonyl)amino]-8-oxononanoic acid methyl ester (1eq.) was dissolved in a 1:1 mixture of THF and water at RT and LiOHhydrate (1.2 eq.) was added and the mixture was stirred for 30 min. Themixture was partitioned between 0.1M HCl and DCM, separated and theorganic phase was washed with water, dried (Na₂SO₄) and concentratedunder reduced pressure. The colourless oil A1 obtained was used in thenext step without purification. MS (ES) C₁₄H₂₅NO₅ requires: 287, found:288 (M+H)⁺.

Step 2:tert-Butyl[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-2-yl)octyl]carbamate (A2)

A solution of A1 (1 eq.) and Cs₂CO₃ (0.5 eq) in EtOH was stirred for 30min at RT and then concentrated under reduced pressure.2-Bromoacetophenone (1 eq.) was added to the resulting salt in DMF andthe mixture was stirred for 1 h at RT under N₂. The DMF was removed byazeotroping with xylene. EtOAc was added, the mixture was filtered andthe residue was washed with EtOAc. The combined filtrates wereconcentrated under reduced pressure. A solution of the resulting oil andammonium acetate (20 eq.) in xylene was heated at reflux (150° C. bathtemperature) for 3 h. The mixture was cooled to RT, diluted with EtOAcand washed with water (×2), sat. aq. NaHCO₃ solution and brine. Thesolution was dried (Na₂SO₄), concentrated under reduced pressure and theresulting brown oil was purified by chromatography on silica gel elutingwith EtOAc/petrol ether (1.5:1) to obtain the imidazole A2 as acolourless oil. ¹H NMR (300 MHz, CDCl₃) δ: 10.50-9.60 (1H, m), 7.82-7.40(2H, m), 7.38-7.29 (2H, m), 7.22-7.15 (2H, m), 5.13 (1H, br. s),4.68-4.55 (1H, m), 2.39 (2H, t, J=7.2 Hz), 2.22-2.06 (4H, m), 1.99-1.80(1H, m), 1.60-1.50 (2H, m), 1.43 (9H, s), 1.40-1.27 (4H, m). MS (ES)C₂₂H₃₁N₃O₃ requires: 385, found: 386 (M+H)⁺.

Step 3: 2-[(1S)-1-Ammonio-7-oxooctyl]-5-phenyl-1H-imidazol-1-iumbis(trifluoroacetate) (A3)

A2 (1 eq.) was dissolved in TFA/DCM (1:1) at 0° C. The cooling bath wasremoved and the mixture was stirred for 60 min at RT. The solvents wereremoved under reduced pressure and the residue was left under highvacuum for a further 3 h. The crude amine salt A3 was used withoutfurther purification. MS (ES) C₁₇H₂₃N₃O requires: 285, found: 286(M+H)⁺.

Step 4:1-Methyl-3-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}carbonyl)piperidiniumbis(trifluoroacetate) (A4)

To a solution of A3 (1 eq.) and Et₃N (2.2 eq.) in DMF was added asolution of EDC.HCl (1.2 eq), HOBt (1.2 eq) and1-methylpiperidine-3-carboxylic acid (1.2 eq) in DMF. The mixture wasshaken at RT for 16 h and the desired material was isolated bypreparative RP-HPLC, using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) aseluents (C18 column). The desired fractions were lyophilized to affordthe imidazole A4 as a colourless oil which solidified upon standing. ¹HNMR (300 MHz, DMSO-d6) δ: 8.96-8.91 (1H, m), 7.98 (1H, s), 7.78 (2H, d,J=7.5 Hz), 7.50 (2H, t, J=7.5 Hz), 7.45-7.32 (1H, m), 5.06-4.90 (1H, m),3.16-2.67 (8H, m), 2.40 (2H, t, J=7.2 Hz), 2.05 (3H, s), 2.03-1.16 (12H,m). MS (ES) C₂₄H₃₄N₄O₂ requires: 410, found: 411 (M+H)⁺.

Example 22-((1S)-1-{[(4-Methoxyphenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-iumtrifluoroacetate (B1)

To a solution of Example 1, A3 and Et₃N (1.1 eq.) in DCM was added4-methoxybenzene sulfonyl chloride (1.1 eq.). The reaction mixture wasstirred at RT for 3 hr and the mixture was washed with sat. aq. NaHCO₃.The organic phase was concentrated under reduced pressure and the cruderesidue was purified by preparative RP-HPLC, using H₂O (0.1% TFA) andMeCN (+0.1% TFA) as eluents (column: C18). The desired fractions werelyophilized to afford the titled compound B1 as a colourless oil. ¹H NMR(300 MHz, CD₃CN) δ: 8.87 (1H, d, J=9.3 Hz), 7.60-7.52 (4H, m), 7.51-7.40(3H, m), 7.31 (1H, s), 6.79-6.63 (2H, m), 4.78-4.65 (1H, m), 3.51 (3H,s), 2.37 (2H, t, J=7.3 Hz), 2.04 (3H, s), 1.89-1.78 (2H, m), 1.51-1.32(3H, m), 1.31-1.14 (3H, m). MS (ES) C₂₄H₂₉N₃O₄S requires: 455, found:456 (M+H)⁺.

Example 32-[(1S)-1-({[[2-(Dimethylammonio)ethyl](methyl)amino]-sulfonyl}amino)-7-oxooctyl]-5-phenyl-1H-imidazol-1-iumbis(trifluoroacetate) (C2) Step 1:2-[(Chlorosulfonyl)(methyl)amino]-N,N-dimethylethanaminium chloride (C1)

To a solution of sulfuryl chloride (1.0 eq.) in CHCl₃ at 0° C. was addeddropwise trimethylethylenediamine (1.0 eq.) over 15 mins. After theaddition, the cooling bath was removed and the mixture was stirredovernight at RT. The solvent was removed under reduced pressure and theresidue was left under high vacuum for 4 h. The crude product wasobtained as a pale yellow solid and was used without furtherpurification. ¹H NMR (300 MHz, DMSO-d6) δ: 3.46-3.29 (4H, m), 2.83 (6H,s), 2.60 (3H, s).

Step 2:2-[(1S)-1-({[[2-(Dimethylammonio)ethyl](methyl)amino]-sulfonyl}amino)-7-oxooctyl]-5-phenyl-1H-imidazol-1-iumbis(trifluoroacetate) (C2)

To a solution Example 1, A3 and Et₃N (4 eq.) in DCM was added crude C1(1.2 eq). The mixture was stirred at RT for 16 hr. The mixture waspurified by preparative RP-HPLC, using H₂O (0.1% TFA) and MeCN (+0.1%TFA) as eluents (column: C18). The desired fractions were lyophilized toafford the titled compound C2 as a colourless oil. ¹H NMR (300 MHz,DMSO-d₆) δ: 8.18 (1H, br. s), 7.87 (1H, br. s), 7.83-7.71 (2H, m),7.58-7.28 (3H, m), 4.64-4.45 (1H, m), 3.41-3.16 (4H, m), 2.79 (6H, s),2.63 (3H, s), 2.39 (2H, t, J=6.8 Hz), 2.05 (3H, s), 1.98-1.78 (2H, m),1.53-1.19 (6H, m). MS (ES) C₂₂H₃₅N₅O₃S requires: 449, found: 450 (M+H)⁺.

Example 42-((1S)-1-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-iumtrifluoroacetate (D1)

To a solution of Example 1, A3 and Et₃N (1 eq.) in DCM was added asolution of EDC hydrochloride (1.2 eq.), HOBt (1.2 eq.) and(5-methoxy-2-methyl-1H-indol-3-yl)acetic acid (1.2 eq.) in DCM. Themixture was shaken at RT for 1.5 hr and then the reaction mixture wasdiluted with DCM, washed with saturated aqueous NaHCO₃, dried (Na₂SO₄),filtered and concentrated under reduced pressure. The crude residue waspurified by preparative RP-HPLC, using H₂O (0.1% TFA) and MeCN (+0.1%TFA) as eluents (column: C18). The desired fractions were lyophilized toafford the titled compound D1 as a white fluffy powder.

¹H NMR (400 MHz, DMSO-d6+TFA) δ: 14.43 (2H, bs), 10.61 (1H, s), 8.59(1H, d, J=6.6 Hz), 8.05 (1H, s), 7.79-7.73 (2H, m), 7.56-7.48 (2H, m),7.47-7.41 (1H, m), 7.10 (1H, d, J=8.6 Hz), 6.96 (1H, d, J=2.4 Hz), 6.60(1H, dd, J=8.6, 2.4 Hz), 5.06-4.97 (1H, m), 3.68 (3H, s), 3.57 (1H, d,J=15.3 Hz), 3.48 (1H, d, J=15.3 Hz), 2.36-2.27 (5H, m), 2.03 (3H, s),1.97-1.83 (2H, m), 1.43-1.13 (6H, m). MS (ES) C₂₉H₃₄N₄O₃ requires: 486,found: 487 (M+H)⁺.

Examples 5-31 were made according to the reaction schemes and theprocesses given in Examples 1-4.

Procedure from Example Name (M + H)⁺ Example Number 51-Methyl-4-(2-oxo-2-{[(1S)-7-oxo-1-(5- 426 1 phenyl-1H-imidazol-1-ium-2-yl)octyl]amino}ethyl)piperazinediium tris(trifluoroacetate) 61-Methyl-2-({[(1S)-7-oxo-1-(5-phenyl-1H- 411 1 imidazol-1-ium-2-yl)octyl]amino}carbonyl)piperidinium bis(trifluoroacetate) 71-(3-Oxo-3-{[(1S)-7-oxo-1-(5-phenyl-1H- 425 1 imidazol-1-ium-2-yl)octyl]amino}propyl)piperidinium bis(trifluoroacetate) 82-((1S)-1-{[(1-Methylpyrrolidinium-3- 397 1yl)carbonyl]amino}-7-oxooctyl)-5-phenyl-1H- imidazol-1-iumbis(trifluoroacetate) 9 1-Methyl-4-({[(1S)-7-oxo-1-(5-phenyl-1H- 411 1imidazol-1-ium-2- yl)octyl]amino}carbonyl)piperidiniumbis(trifluoroacetate) 10 2-{(1S)-7-Oxo-1-[(2- 396 1thienylcarbonyl)amino]octyl}-5-phenyl-1H- imidazol-1-iumtrifluoroacetate 11 2-{(1S)-7-Oxo-1-[(1,3-thiazol-5- 397 1ylcarbonyl)amino]octyl}-5-phenyl-1H- imidazol-1-ium trifluoroacetate 122-((1S)-1-{[(4-Methyl-1,2,3-thiadiazol-5- 412 1yl)carbonyl]amino}-7-oxooctyl)-5-phenyl-1H- imidazol-1-iumtrifluoroacetate 13 2-{(1S)-1-[(2,3-Dihydro-1,4-benzodioxin-6- 484 2ylsulfonyl)amino]-7-oxooctyl}-5-phenyl-1H- imidazol-1-iumtrifluoroacetate 14 2-(1-{[(5-Methoxy-2-methyl-1H-indol-3- 487 4yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H- imidazol-1-iumtrifluoroacetate 15 2-((1S)-1-{[(4-Cyanophenyl)sulfonyl] 451 2amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1- ium trifluoroacetate 162-{(1S)-1-[(2-Naphthylsulfonyl) 476 2amino]-7-oxooctyl}-5-phenyl-1H-imidazol-1- ium trifluoroacetate 172-((1S)-1-{[(2,4-Dimethyl-1,3-thiazol-5- 461 2yl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H- imidazol-1-iumtrifluoroacetate 18 2-{(1S)-1-[(1-Benzothien-3-ylsulfonyl)amino]- 482 27-oxooctyl}-5-phenyl-1H-imidazol-1-ium trifluoroacetate 192-((1S)-1-{[(4-Chlorophenyl)sulfonyl] 460 2amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1- ium trifluoroacetate 202-((1S)-1-{[(3-Methoxyphenyl) 456 2sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H- imidazol-1-ium trifluoroacetate21 1,2-Dimethyl-4-({[(1S)-7-oxo-1-(5-phenyl-1- 444 2imidazol-1-ium-2-yl)octyl]amino}sulfonyl)- 1H-imidazol-1-iumbis(trifluoroacetate) 22 2-((1S)-1-{[(3,5-Dimethylisoxazol-4- 445 2yl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H- imidazol-1-iumtrifluoroacetate 23 4-[({1-[5-(2-Methoxyphenyl)-1H-imidazol-1- 441 1ium-2-yl]-7-oxooctyl}amino)carbonyl]-1- methylpiperidiniumbis(trifluoroacetate) 24 4-[({1-[5-(3-Methoxyphenyl)-1H-imidazol-1- 4411 ium-2-yl]-7-oxooctyl}amino)carbonyl]-1- methylpiperidiniumbis(trifluoroacetate) 25 4-[({1-[5-(4-Fluorophenyl)-1H-imidazol-1- 429 1ium-2-yl]-7-oxooctyl}amino)carbonyl]-1- methylpiperidiniumbis(trifluoroacetate) 26 4-[({1-[5-(4-Chlorophenyl)-1H-imidazol-1- 445 1ium-2-yl]-7-oxooctyl}amino)carbonyl]-1- methylpiperidiniumbis(trifluoroacetate) 27 4-[({1-[5-(4-Bromophenyl)-1H-imidazol-1- 489 1ium-2-yl]-7-oxooctyl}amino)carbonyl]-1- methylpiperidiniumbis(trifluoroacetate) 28 4-[({1-[5-(2-Chlorophenyl)-1H-imidazol-1- 445 1ium-2-yl]-7-oxooctyl}amino)carbonyl]-1- methylpiperidiniumbis(trifluoroacetate) 29 4-[({1-[5-(3,4-Dichlorophenyl)-1H-imidazol- 4791 1-ium-2-yl]-7-oxooctyl}amino)carbonyl]-1- methylpiperidiniumbis(trifluoroacetate) 30 4-[({1-[5-(4-Cyanophenyl)-1H-imidazol-1- 436 1ium-2-yl]-7-oxooctyl}amino)carbonyl]-1- methylpiperidiniumbis(trifluoroacetate) 31 4-[({1-[5-(3-Cyanophenyl)-1H-imidazol-1- 436 1ium-2-yl]-7-oxooctyl}amino)carbonyl]-1- methylpiperidiniumbis(trifluoroacetate)

ExampleS 32 and 334-({[(1S)-1-(4,5-Diphenyl-1,3-oxazol-2-yl)-7-oxooctyl]amino}carbonyl)-1-methylpiperidiniumtrifluoroacetate (E2a) and4-({[(1S)-1-(4,5-Diphenyl-1H-imidazol-1-ium-2-yl)-7-oxooctyl]amino}carbonyl)-1-methylpiperidiniumbis(trifluoroacetate) (E2b) Step 1: tert-Butyl[(1S)-1-(4,5-diphenyl-1,3-oxazol-2-yl)-7-oxooctyl]carbamate (E1a) andtert-butyl [(1S)-1-(4,5-diphenyl-1,3-imidazol-2-yl)-7-oxooctyl]carbamate(E1b)

A solution of Example 1, Al and Cs₂CO₃ (0.5 eq) in EtOH was stirred atRT for 30 min and was then concentrated to dryness under reducedpressure. To the resulting salt dissolved in DMF was added2-bromo-1,2-diphenylethanone (1 eq.). The resulting mixture was stirredfor 1 hr at RT and then the DMF was removed under reduced pressure.EtOAc was added and the mixture was filtered and the filter was washedwith further EtOAc. The combined filtrates were concentrated underreduced pressure. A solution of the resulting oil and NH₄OAc (20 eq.) inxylene was heated at reflux (150° C. bath temperature) for 90 min andwas then cooled to RT and diluted with EtOAc. The solution was washedwith H₂O (2×), sat. aq. NaHCO₃, and brine, then dried (Na₂SO₄) andconcentrated under reduced pressure. The resulting brown oil was used inthe next step without further purification.

tert-Butyl [(1S)-1-(4,5-diphenyl-1,3-oxazol-2-yl)-7-oxooctyl]carbamate:MS (ES) C₂₈H₃₄N₂O₄ requires: 462, found: 463 (M+H)⁺.

tert-Butyl[(1S)-1-(4,5-diphenyl-1,3-imidazol-2-yl)-7-oxooctyl]carbamates: MS (ES)C₂₈H₃₅N₃O₃ requires: 461, found: 462 (M+H)⁺.

Step 2:4-({[(1S)-1-(4,5-Diphenyl-1,3-oxazol-2-yl)-7-oxooctyl]amino}-carbonyl)-1-methylpiperidiniumtrifluoroacetate (E2a) and4-({[(1S)-1-(4,5-Diphenyl-1H-imidazol-1-ium-2-yl)-7-oxooctyl]amino}carbonyl)-1-methylpiperidiniumbis(trifluoroacetate) (E2b)

The mixture of carbamates from the previous step (E1a and E1b) wasdissolved in TFA/DCM (1:1) and the mixture was stirred for 60 min at RT.The solvents were removed under vacuum and the residue was partitionedbetween sat. aq. NaHCO₃ and DCM. The organic phase was dried (Na₂SO₄)and concentrated under reduced pressure. To the obtained residue wasadded a solution of EDC.HCl (1.2 eq), HOBt (1.2 eq) and4-carboxy-1-methylpiperidinium chloride (1.2 eq) in DMF, followed byEt₃N (1.2 eq). The mixture was stirred at RT for 4 hr. The products wereisolated by preparative RP-HPLC, using H₂O (0.1% TFA) and MeCN (+0.1%TFA) as eluents (column: C18), to yield first the imidazole E2a and thenthe oxazole E2b. The desired fractions were lyophilized to afford thetitled compounds as colourless oils.

Eluted first:(4-({[(1S)-1-(4,5-Diphenyl-1H-imidazol-1-ium-2-yl)-7-oxooctyl]amino}carbonyl)-1-methylpiperidinium bis(trifluoroacetate): MS (ES) C₃₀H₃₈N₄O₂ requires: 486,found: 487 (M+H)⁺.

Eluted second:4-({[(1S)-1-(4,5-diphenyl-1,3-oxazol-2-yl)-7-oxooctyl]amino}-carbonyl)-1-methylpiperidiniumtrifluoroacetate: ¹H NMR (300 MHz, DMSO-d6) δ: 9.50-9.13 (1H, m), 8.63(1H, d, J=8.2 Hz), 7.65-7.30 (10H, m), 5.01 (1H, m), 3.51-3.24 (2H, m),3.22-2.84 (2H, m), 2.82-2.70 (3H, m), 2.55-2-45 (1H, m), 2.41 (2H, t,J=3.6 Hz), 2.05 (3H, s), 2.02-1.64 (6H, m), 1.54-1.19 (6H, m). MS (ES)C₃₀H₃₇N₃O₃ requires: 487, found: 488 (M+H)⁺.

Examples 34-86 were made according to the reaction schemes and theprocesses given in Examples 14, 32 and 33.

Procedure from Example Example Name (M + H)⁺ Number 342-((1S)-1-{[(5-Methoxy-2-methyl-1H-indol-3- 487 1yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol- 1-ium chloride 351-Methyl-4-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol- 411 11-ium-2-yl)octyl]amino}carbonyl)piperidinium dichloride 361-Methyl-4-[4-({[(1S)-7-oxo-1-(5-phenyl-1H- 488 1 imidazol-1-ium-2-yl)octyl]amino}carbonyl)phenyl]piperazinediium tris(trifluoroacetate) 373-({[(1S)-7-Oxo-1-(5-phenyl-1H-imidazol-1-ium-2- 474 1yl)octyl]amino}carbonyl)-1-pyridin-2-ylpiperidiniumbis(trifluoroacetate) 383-(2-Oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazol- 466 11-ium-2-yl)octyl]amino}ethyl)-6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidin-4-ium bis(trifluoroacetate) 392-(3-Oxo-3-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazol- 437 11-ium-2-yl)octyl]amino}propyl)-2- azoniabicyclo[2.2.1]heptanebis(trifluoroacetate) 404-(2-Oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazol- 490 11-ium-2-yl)octyl]amino}-1-pyridinium-3- ylethyl)morpholin-4-iumtris(trifluoroacetate) 41 1-Methyl-4-({[(1S)-1-(4-methyl-5-phenyl-1H-425 32 imidazol-1-ium-2-yl)-7- oxooctyl]amino}carbonyl)piperidiniumbis(trifluoroacetate) 424-({[(1S)-1-(5-Biphenyl-4-yl-1H-imidazol-1-ium-2- 487 1yl)-7-oxooctyl]amino}carbonyl)-1- methylpiperidiniumbis(trifluoroacetate) 431-Methyl-4-[({(1S)-1-[5-(2-naphthyl)-1H-imidazol- 461 1 1-ium-2-yl]-7-oxooctyl}amino)carbonyl]piperidinium bis(trifluoroacetate) 444-[({(1S)-1-[5-(3-Chlorophenyl)-1H-imidazol-1- 445 1ium-2-yl]-7-oxooctyl}amino)carbonyl]-1- methylpiperidiniumbis(trifluoroacetate) 454-{[((1S)-1-{5-[3,5-bis(Trifluoromethyl)phenyl]-1H- 547 1imidazol-1-ium-2-yl}-7-oxooctyl)amino]carbonyl}- 1-methylpiperidiniumbis(trifluoroacetate) 46 1-Methyl-4-{[((1S)-7-oxo-1-{5-[3- 479 1(trifluoromethyl)phenyl]-1H-imidazol-1-ium-2-yl}octyl)amino]carbonyl}piperidinium bis(trifluoroacetate) 472-((1S)-1-{[(3-Cyanophenyl)sulfonyl]amino}-7- 451 2oxooctyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 482-{(1S)-7-Oxo-1-[(phenylsulfonyl)amino]octyl}-5- 426 2phenyl-1H-imidazol-1-ium trifluoroacetate 494-Methyl-7-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol- 497 21-ium-2-yl)octyl]amino}sulfonyl)-3,4-dihydro-2H- 1,4-benzoxazin-4-iumbis(trifluoroacetate) 502-[(1S)-1-({[2-(Acetylamino)-4-methyl-1,3-thiazol- 504 25-yl]sulfonyl}amino)-7-oxooctyl]-5-phenyl-1H- imidazol-1-iumtrifluoroacetate 51 2-((1S)-1-{[(5-Chloro-2-thienyl)sulfonyl]amino}-7-466 2 oxooctyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 521,3,5-Trimethyl-4-({[(1S)-7-oxo-1-(5-phenyl-1H- 458 2imidazol-1-ium-2-yl)octyl]amino}sulfonyl)-1H- pyrazol-1-iumbis(trifluoroacetate) 53 2-[(1S)-1-({[5-(2-Methyl-1,3-thiazol-4-yl)-2-529 2 thienyl]sulfonyl}amino)-7-oxooctyl]-5-phenyl-1H- imidazol-1-iumtrifluoroacetate 54 2-{(1S)-1-[({5-[1-Methyl-3-(trifluoromethyl)-1H- 5802 pyrazol-5-yl]-2-thienyl}sulfonyl)amino]-7-oxooctyl}-5-phenyl-1H-imidazol-1-ium trifluoroacetate 552-((1S)-1-{[(5-Isoxazol-3-yl-2- 499 2thienyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl-1H- imidazol-1-iumtrifluoroacetate 56 1-Methyl-4-{[((1S)-7-oxo-1-{5-[4- 479 1(trifluoromethyl)phenyl]-1H-imidazol-1-ium-2-yl}octyl)amino]carbonyl}piperidinium bis(trifluoroacetate) 574-{[((1S)-1-{5-[4-(Difluoromethoxy)phenyl]-1H- 477 1imidazol-1-ium-2-yl}-7-oxooctyl)amino]carbonyl}- 1-methylpiperidiniumbis(trifluoroacetate) 584-[({(1S)-1-[5-(3,4-Difluorophenyl)-1H-imidazol-1- 447 1ium-2-yl]-7-oxooctyl}amino)carbonyl]-1- methylpiperidiniumbis(trifluoroacetate) 59 2-((1S)-1-{[(2-Nitrophenyl)sulfonyl]amino}-7-471 2 oxooctyl)-5-phenyl-1H-imidazol-3-ium trifluoroacetate 602-((1S)-1-{[(3-Nitrophenyl)sulfonyl]amino}-7- 471 2oxooctyl)-5-phenyl-1H-imidazol-3-ium trifluoroacetate 61 2-[(1S)-1-({[4-483 2 (Acetylamino)phenyl]sulfonyl}amino)-7-oxooctyl]-5-phenyl-1H-imidazol-3-ium trifluoroacetate 622-((1S)-1-{[(2-Cyanophenyl)sulfonyl]amino}-7- 451 2oxooctyl)-5-phenyl-1H-imidazol-3-ium trifluoroacetate 632-((1S)-1-{[(2-Chloro-4- 485 2cyanophenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl- 1H-imidazol-3-iumtrifluoroacetate 64 2-((1S)-1-{[(3-Fluoro-4- 489 2nitrophenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl- 1H-imidazol-3-iumtrifluoroacetate 65 2-[(1S)-1-({[2-(Methoxycarbonyl)-3- 490 2thienyl]sulfonyl}amino)-7-oxooctyl]-5-phenyl-1H- imidazol-3-iumtrifluoroacetate 66 2-((1S)-1-{[(2,5-Dimethoxyphenyl)sulfonyl]amino}-486 2 7-oxooctyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 672-((1S)-1-{[(3-Fluorophenyl)sulfonyl]amino}-7- 444 2oxooctyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 682-((1S)-1-{[(3-Cyano-4- 469 2fluorophenyl)sulfonyl]amino}-7-oxooctyl)-5-phenyl- 1H-imidazol-1-iumtrifluoroacetate 69 2-[(1S)-1-({[4- 492 2(Difluoromethoxy)phenyl]sulfonyl}amino)-7-oxooctyl]-5-phenyl-1H-imidazol-1-ium trifluoroacetate 70 2-[(1S)-1-({[3-492 2 (Difluoromethoxy)phenyl]sulfonyl}amino)-7-oxooctyl]-5-phenyl-1H-imidazol-1-ium trifluoroacetate 712-{(1S)-1-[(2,1,3-Benzothiadiazol-5- 484 2ylsulfonyl)amino]-7-oxooctyl}-5-phenyl-1H- imidazol-1-iumtrifluoroacetate 72 2-{(1S)-1-[(2,3-Dihydro-1-benzofuran-5- 468 2ylsulfonyl)amino]-7-oxooctyl}-5-phenyl-1H- imidazol-1-iumtrifluoroacetate 73 2-Morpholin-4-yl-5-({[(1S)-7-oxo-1-(5-phenyl-1H- 5122 imidazol-1-ium-2- yl)octyl]amino}sulfonyl)pyridiniumbis(trifluoroacetate) 74 2-{(1S)-1-[(2,1,3-Benzoxadiazol-4- 468 2ylsulfonyl)amino]-7-oxooctyl}-5-phenyl-1H- imidazol-1-iumtrifluoroacetate 75 2-((1S)-1-{[(4-Fluorophenyl)sulfonyl]amino}-7- 444 2oxooctyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 762-((1S)-1-{[(4-Nitrophenyl)sulfonyl]amino}-7- 471 2oxooctyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 772-((1S)-1-{[(2-Fluorophenyl)sulfonyl]amino}-7- 444 2oxooctyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 782-((1S)-1-{[(3,4-Dimethoxyphenyl)sulfonyl]amino}- 486 27-oxooctyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 792-((1S)-1-{[(3,4-Difluorophenyl)sulfonyl]amino}-7- 462 2oxooctyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 805-({[(1S)-7-Oxo-1-(5-phenyl-1H-imidazol-1-ium-2- 477 2yl)octyl]amino}sulfonyl)isoquinolinium bis(trifluoroacetate) 812-((1S)-1-{[(4-Carboxyphenyl)sulfonyl]amino}-7- 470 2oxooctyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 821-Methyl-4-[({(1S)-7-oxo-1-[5-(3-thienyl)-1H- 417 1 imidazol-3-ium-2-yl]octyl}amino)carbonyl]piperidinium bis(trifluoroacetate) 832-[2-((1S)-1-{[(1-Methylpiperidinium-4- 412 1yl)carbonyl]amino}-7-oxooctyl)-1H-imidazol-3-ium- 5-yl]pyridiniumtris(trifluoroacetate) 844-[({(1S)-1-[5-(5-Chloro-3-methyl-1-benzothien-2- 515 1yl)-1H-imidazol-3-ium-2-yl]-7-oxooctyl}amino)carbonyl]-1-methylpiperidinium bis(trifluoroacetate) 851-Methyl-4-[({(1S)-7-oxo-1-[5-(3-phenylisoxazol-5- 478 1yl)-1H-imidazol-3-ium-2- yl]octyl}amino)carbonyl]piperidiniumbis(trifluoroacetate) 86 1-Methyl-4-{[((1S)-1-{5-[6-methyl-2- 540 1(trifluoromethyl)[1,3]thiazolo[3,2-b][1,2,4]triazol-5-yl]-1H-imidazol-3-ium-2-yl}-7- oxooctyl)amino]carbonyl}piperidiniumbis(trifluoroacetate)

Example 871-Methyl-4-[({(1S)-1-[1-methyl-4-(2-naphthyl)-1H-imidazol-3-ium-2-yl]-7-oxooctyl}amino)carbonyl]piperidiniumbis(trifluoroacetate) (F3) Step 1: 2-(2-Naphthyl)-2-oxoethyl(2S)-2-[(tert-butoxycarbonyl)amino]-8-oxo nonanoate (F1)

A solution of Example 1, Al and Cs₂CO₃ (0.5 eq) in EtOH was stirred for30 min at RT and was then concentrated to dryness under reducedpressure. To the resulting salt in DMF was added2-bromo-1-(2-naphthyl)ethanone (1 eq.). The mixture was stirred for 1 hrat RT and the DMF was removed under reduced pressure. EtOAc was added,the mixture was filtered and the filter was washed with EtOAc. Thecombined filtrates were concentrated under reduced pressure. Thecolourless oil obtained was used in the next step without purification.MS (ES) C₂₆H₃₃NO₆ requires: 455, found: 456 (M+H)⁺.

Step 2:2-{(1S)-1-[(tert-Butoxycarbonyl)amino]-7-oxooctyl}-1-methyl-4-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate (F2)

To a solution of F1 in xylene was added NH₄OAc (10 eq.) and MeNH₃OAc (10eq.). The mixture was heated at reflux (150° C. bath temperature) for 90min. After cooling to RT, the mixture was diluted with EtOAc and washedwith H₂O and sat. aq. NaHCO₃. The organic phase was concentrated underreduced pressure and the desired product was isolated by preparativeRP-HPLC, using water (0.1% TFA) and MeCN (0.1% TFA) as eluents (column:C18). The desired fractions were lyophilized to afford the product ascolourless oil. MS (ES) C₂₇H₃₅N₃O₃ requires: 449, found: 450 (M+H)+

Step 3:1-Methyl-4-[({(1S)-1-[1-methyl-4-(2-naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]piperidiniumbis(trifluoroacetate) (F3)

F2 was dissolved in TFA/DCM (1:1) and the mixture was stirred for 60 minat RT. The solvents were removed under reduced pressure and the residuewas partitioned between sat. aq. NaHCO₃ and DCM. The organic phase wasseparated, dried (Na₂SO₄) and concentrated under reduced pressure.

To the resulting residue was added a solution of EDC.HCl (1.2 eq), HOBt(1.2 eq) and 4-carboxy-1-methylpiperidinium chloride (1.2 eq) in DMF,followed by DIPEA (1.2 eq.). The mixture was stirred at RT for 2 hr andthen the product F3 was isolated by preparative RP-HPLC, using water(0.1% TFA) and MeCN (0.1% TFA) as eluents (column: C18). The desiredfractions were lyophilized to afford the final product as a colourlessoil. ¹H NMR (300 MHz, DMSO-d6) δ: 9.62-9.20 (1H, m), 8.69 (1H, s), 8.29(1H, s), 8.01-7.81 (5H, m), 7.59-7.44 (2H, m), 5.05 (1H, m), 3.77 (3H,s), 3.50-3.22 (2H, m), 3.20-2.82 (2H, m), 2.81-2.70 (3H, m), 2.55-2.45(1H, m), 2.41 (2H, t, J=3.6 Hz), 2.06 (3H, s), 2.02-1.64 (6H, m),1.54-1.19 (6H, m). MS (ES) C₂₉H₃₈N₄O₂ requires: 474, found: 475 (M+H)⁺.

Example 882-(5-Methoxy-2-methyl-1H-indol-3-yl)-N-{(1S)-1-[5-(2-naphthyl)-4H-1,2,4-triazol-3-yl]-7-oxononyl}acetamide(G5) Step 1: Methyl(2S)-2-[(tert-butoxycarbonyl)amino]-8-hydroxydecanoate (G1)

To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-8-oxodecanoic acidin anhydrous THF at 0° C. under a nitrogen atmosphere was added slowly asolution of BH₃.Me₂S in THF (2 M, 2 eq.). The mixture was stirred for 5min at 0° C. and 3 hr at 55° C. The reaction was quenched with MeOH andpartitioned between EtOAc and sat. aq. NaHCO₃. The organic phase wasdried (Na₂SO₄) and concentrated under reduced pressure. The obtainedproduct was used in the next step without purification. MS (ES)C₁₆H₃₁NO₅ requires: 317, found: 318 (M+H)⁺.

Step 2: (2S)-2-[(tert-Butoxycarbonyl)amino]-8-hydroxydecanohydrazide(G2)

G1 was dissolved in ^(i)PrOH and NH₂NH₂.H₂O (3 eq.) was added, themixture was then heated at 80° C. for 16 hr. The mixture was cooled toRT and partitioned between DCM and H₂O. The organics were washed withbrine, dried (Na₂SO₄) and concentrated under reduced pressure. The crudeproduct was used in the next step without purification. MS (ES)C₁₅H₃₁N₃O₄ requires: 317, found: 318 (M+H)⁺.

Step 3: tert-Butyl{(1S)-7-Hydroxy-1-[3-(2-naphthyl)-1H-1,2,4-triazol-5-yl]nonyl}carbamate(G3)

To a solution of the 2-naphthonitrile in anhydrous MeOH was addeddropwise a solution of NaOMe in MeOH (31%, 1 eq.). The mixture waswarmed to 40° C. for 5 min and then left to stir at RT for 1 hr. Themixture was left standing at 5° C. overnight and then neutralized withAcOH and added to G2. The resulting mixture was stirred for 3 hr at RT.The solvent was removed under reduced pressure and the residue wassuspended in anhydrous toluene and was heated to 110° C. for 2.5 hr.After cooling to RT, the mixture was partitioned between EtOAc andwater. The organic phase was washed with brine, dried (Na₂SO₄) andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica using 50% EtOAc/petroleum ether as eluent togive the desired product was obtained as a colourless oil. MS (ES)C₂₆H₃₆N₄O₃ requires: 452, found: 453 (M+H)⁺.

Step 4: tert-Butyl{(1S)-1-[3-(2-Naphthyl)-1H-1,2,4-triazol-5-yl]-7-oxononyl}carbamate (G4)

To a solution of G3 in anhydrous DCM was added Dess-Martin periodinane(1.5 eq.). The mixture was stirred for 2 hr at RT and then a sat. aq.NaHCO₃ (containing Na₂S₂O₃ (6 eq.)) was added and the mixture wasstirred for 15 min. The phases were separated and the H₂O phase waswashed with DCM. The combined organic phases were dried (Na₂SO₄) andconcentrated under reduced pressure. The obtained product was used inthe next step without further purification. MS (ES) C₂₆H₃₄N₄O₃ requires:450, found: 451 (M+H)⁺.

Step 5:2-(5-Methoxy-2-methyl-1H-indol-3-yl)-N-{(1S)-1-[3-(2-naphthyl)-1H-1,2,4-triazol-5-yl]-7-oxononyl}acetamide(G5)

G4 was dissolved in a mixture of DCM and TFA (1:1) and stirred at RT.After 20 min, the solvents were removed under reduced pressure and theresidue was partitioned between DCM and sat. aq. NaHCO₃. The organicphase was separated, dried (Na₂SO₄) and concentrated under reducedpressure.

To the residue was added a solution of(5-methoxy-2-methyl-1H-indol-3-yl)acetic acid (1.3 eq.), HOBt (1.3 eq.)and EDC.HCl (1.3 eq.) in DMF (premixed for 3 min), followed by DIPEA(1.3 eq.). The mixture was left stirring at room temperature for 3 hr.The product was isolated by preparative RP-HPLC, using water (0.1% TFA)and acetonitrile (0.1% TFA) as eluents (column: C18), the desiredfractions were lyophilized to afford the final product as a colourlessoil. ¹H NMR (300 MHz, DMSO-d6) δ: 10.57 (1H, s), 8.52 (1H, s), 8.39 (1H,d, J=7.5 Hz), 8.18-7.18 (4H, m), 7.65-7.49 (2H, m), 7.16-6.98 (2H, m),6.64-6.54 (1H, m), 5.00 (1H, m), 3.67 (3H, s), 3.60-3.40 (2H, m),2.40-2.23 (7H, m), 1.98-1.72 (2H, m), 1.45-1.11 (6H, m), 0.89 (3H, t,J=7.3 Hz). MS (ES) C₃₃H₃₇N₅O₃ requires: 551, found: 552 (M+H)⁺.

Example 892-(5-Methoxy-2-methyl-1H-indol-3-yl)-N-[7-oxo-1-(4-phenyl-2-thienyl)nonyl]acetamide(H4) Step 1:6-(2-Ethyl-1,3-dioxolan-2-yl)-1-(4-phenyl-2-thienyl)hexan-1-ol (H1)

To a stirred mixture of Mg (2.5 eq.) in anhydrous THF under Ar was added12 (>5 mol %) and the mixture heated at reflux until the solution becamecolourless. Then 2-(5-bromopentyl)-2-ethyl-1,3-dioxolane (2.2 eq.)[Sanghee, K. et al Synthesis 2003, 14, 2194-2198] was added dropwise,upon complete addition the mixture was heated at reflux for 2.5 hr. Theresulting Grignard reagent obtained was used immediately for the nextstep.

The resulting Grignard solution was added to a solution of4-phenylthiophene-2-carbaldehyde (1 eq.) in THF at 0° C. under Ar andthe mixture was stirred for 30 min. The reaction was quenched by slowaddition of sat. NH₄Cl solution and the desired product was extractedwith EtOAc. The organic layer was washed with brine, dried (Na₂SO₄) andconcentrated under reduced pressure. The crude was purified by columnchromatography eluting with 90% Petroleum ether/EtOAc to afford thedesired alcohol H1. ¹H NMR (300 MHz, CD₃CN) δ: 7.60-7.50 (2H, d, J=7.3Hz), 7.42-7.32 (3H, m), 7.33-7.27 (2H, m), 5.05-4.89 (1H, t, J=7.3 Hz),4.88-4.83 (1H, s), 3.94-3.89 (4H, s), 1.89-1.78 (2H, m), 1.65-1.55 (4H,m), 1.40-1.25 (6H, m), 0.90-0.80 (3H, m). MS (ES) C₂₁H₂₈O₃S requires:360, found: 361 (M+H)⁺.

Step 2: 2-[6-Azido-6-(4-phenyl-2-thienyl)hexyl]-2-ethyl-1,3-dioxolane(H2)

The alcohol H1 was dissolved in toluene, to give a solution of 0.5 M,together with diphenylphosphorazide (DPPA, 1.2 eq.) and then DBU (1.2eq.) was added and the mixture was heated with stirring at 50° C.overnight. After cooling to RT, EtOAc was added and the mixture waswashed with H₂O and then with 5% HCl solution. The organic layer waswashed with brine, dried (Na₂SO₄) and concentrated under reducedpressure. The residue was purified by column chromatography eluting with50% Petroleum ether/EtOAc to afford H2. ¹H NMR (300 MHz, CDCl₃) δ:7.62-7.55 (2H, d, J=8.1 Hz), 7.45-7.20 (5H, m), 4.65 (1H, t, J=7.3 Hz),3.95 (4H, s), 1.89-1.78 (2H, m), 1.65-1.55 (4H, m), 1.45-1.25 (6H, m),0.9-0.8 (3H, m). MS (ES) C₂₁H₂₇N₃O₂S requires: 385, found: 386 (M+H)⁺.

Step 3: [6-(2-Ethyl-1,3-dioxolan-2-yl)-1-(4-phenyl-2-thienyl)hexyl]amine(H3)

The azide H2 was dissolved in MeOH and stirred in the presence of 10%Pd/C under an H2 atmosphere for 1 hr. The H2 atmosphere removed and N₂introduced. The reaction mixture was filtered and the catalyst washedwith MeOH and the filtrates concentrated under reduced pressure. Theresidue was purified by column chromatography eluting with 30% Petroleumether/EtOAc to afford the amine H3. ¹H NMR (300 MHz, CDCl₃) δ: 7.54 (2H,d, J=7.6 Hz), 7.45-7.35 (3H, m), 7.33-7.28 (2H, m), 4.67 (1H, t, J=7.0Hz), 3.90 (4H, s), 1.89-1.78 (2H, m), 1.65-1.55 (4H, m), 1.45-1.25 (6H,m), 0.90-0.80 (3H, m). MS (ES) C₂₁H₂₉NO₂S requires: 359, found: 360(M+H)⁺.

Step 4:2-(5-Methoxy-2-methyl-1H-indol-3-yl)-N-[7-oxo-1-(4-phenyl-2-thienyl)nonyl]acetamide(H4)

To a stirred solution of (5-methoxy-2-methyl-1-indol-3-yl)acetic acid(1.2 eq.), HOBt (1.2 eq.) and EDCI (1.2 eq.) in DCM was added H3. Themixture was stirred at RT for 16 hr. The reaction mixture was washedsuccessively with 0.25 M HCl solution, 0.25 M NaOH solution and brine,dried (Na₂SO₄) and concentrated under reduced pressure. The resultingN-[6-(2-ethyl-1,3-dioxolan-2-yl)-1-(4-phenyl-2-thienyl)hexyl]-2-(5-methoxy-2-methyl-1H-indol-3-yl)acetamidetaken up in 1M HCl solution (4 eq.) and THF and was stirred at RT for 4hr. The mixture neutralized with 1 M NaOH and the ketone was extractedwith EtOAc. The organics were washed with brine and concentrated underreduced pressure. The mixture was purified by preparative RP-HPLC, usingH₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18). Thedesired fractions were lyophilized to afford the titled compound H4 as acolourless oil. ¹H NMR (300 MHz, CD₃CN) δ: 9.00-8.90 (1H, br. s), 7.52(2H, d, J=7.3 Hz), 7.43-7.34 (3H, m), 7.32-7.22 (1H, m), 7.18 (1H, d,J=8.5 Hz), 7.10 (1H, s), 6.97 (1H, s), 6.69 (1H, dd, J=8.6, 2.0 Hz),6.60 (1H, d, J=8.6 Hz), 5.17 (1H, q, J=6.0 Hz), 3.76 (3H, s), 3.56-3.50(2H, br. s), 2.45-2.30 (7H, m), 1.90-1.20 (8H, m), 0.93 (3H, t, J=7.3Hz). MS (ES) C₃₁H₃₆N₂O₃S requires: 516, found: 517

Procedure from Example Name (M + H)⁺ Example Number 904-[({(1S)-1-[5-(1-Benzothien-3-yl)-1H-imidazol-1- 467 1ium-2-yl]-7-oxooctyl}amino)carbonyl]-1- methylpiperidiniumbis(trifluoroacetate) 91 2-{(1S)-1-[(3,4-Difluorobenzoyl)amino]-7- 426 1oxooctyl}-5-phenyl-1H-imidazol-1-ium trifluoroacetate 922-((1S)-1-{[4-(Acetylamino)benzoyl]amino}-7- 447 1oxooctyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 932-((1S)-1-{[4-(Aminosulfonyl)benzoyl]amino}-7- 469 1oxooctyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 944-({[(1S)-7-Oxo-1-(5-phenyl-1H-imidazol-1-ium-2- 391 1yl)octyl]amino}carbonyl)pyridinium bis(trifluoroacetate) 953-({[(1S)-7-Oxo-1-(5-phenyl-1H-imidazol-1-ium-2- 391 1yl)octyl]amino}carbonyl)pyridinium bis(trifluoroacetate) 962-((1S)-1-{[(3,5-Dimethylisoxazol-4- 409 1yl)carbonyl]amino}-7-oxooctyl)-5-phenyl-1H- imidazol-1-iumtrifluoroacetate 97 2-{(1S)-1-[(2,3-Dihydro-1,4-benzodioxin-6- 448 1ylcarbonyl)amino]-7-oxooctyl}-5-phenyl-1H- imidazol-1-iumtrifluoroacetate 98 2-{(1S)-1-[(3-Nitrobenzoyl)amino]-7-oxooctyl}-5- 4351 phenyl-1H-imidazol-1-ium trifluoroacetate 992-{(1S)-1-[(3-Cyanobenzoyl)amino]-7-oxooctyl}-5- 415 1phenyl-1H-imidazol-1-ium trifluoroacetate 1002-{(1S)-1-[(4-Cyanobenzoyl)amino]-7-oxooctyl}-5- 415 1phenyl-1H-imidazol-1-ium trifluoroacetate 1011-Methyl-4-({[7-oxo-1-(4-phenyl-2- 441 89thienyl)nonyl]amino}carbonyl)piperidinium trifluoroacetate 1024-[({(1S)-6-Carboxy-1-[5-(2-naphthyl)-1H-imidazol- 463 1071-ium-2-yl]hexyl}amino)carbonyl]-1- methylpiperidiniumbis(trifluoroacetate) 103 2-((1S)-6-Carboxy-1-{[(3- 523 326nitrophenyl)sulfonyl]amino}hexyl)-5-(2-naphthyl)- 1H-imidazol-1-iumtrifluoroacetate 104 4-[({(1S)-6-Carboxy-1-[5-(3-methoxyphenyl)-1H- 443107 imidazol-1-ium-2-yl]hexyl}amino)carbonyl]-1- methylpiperidiniumbis(trifluoroacetate) 105 2-((1S)-6-Carboxy-1-{[(5-methoxy-2-methyl-1H-519 107 indol-3-yl)acetyl]amino}hexyl)-5-(3-methoxyphenyl)-1H-imidazol-1-ium trifluoroacetate 1062-((1S)-6-Carboxy-1-{[(3- 503 107nitrophenyl)sulfonyl]amino}hexyl)-5-(3- methoxyphenyl)-1H-imidazol-1-iumtrifluoroacetate

Example 1072-((1S)-6-Carboxy-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}hexyl)-5-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate (I6) Step 1: tert-Butyl6-[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]hexanoate(I1)

To a stirred solution of(2R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1.0 eq.) in THF at−78° C., was added dropwise over 10 min a solution of BuLi (1.6 N inhexane, 1.0 eq.) and stirring was continued at −78° C. for 45 min. Apre-cooled solution of tert-butyl 6-iodohexanoate (1.0 eq.) in THF wasthen added by cannula over 5 min and the reaction stirred overnight,slowly warming to RT. The reaction was then left to stir at RT for afurther hour and was quenched by the addition of aqueous NH₄Cl solution.The THF layer was decanted off and concentrated under reduced pressure,meanwhile and the aqueous mixture was extracted with EtOAc (3×). TheEtOAc extracts were used to redissolve the oily THF residue and thissolution was washed with brine, dried (Na₂SO₄) and concentrated underreduced pressure. The crude was used directly in the next step withoutfurther purification (I1).

Step 2: 8-tert-Butyl 1-methyl(2S)-2-[(tert-butoxycarbonyl)amino]octanedioate (I2)

I1 was dissolved in THF (0.12 M solution) and cooled at 0° C. with anice-bath; 1M HCl (4 eq.) was added and the mixture was stirred 20 min atthe same temperature. 1M NaOH was added (4 eq), the aqueous phase wasextracted with EtOAc and the collected organic phases were treated withbrine, dried (Na₂SO₄), then solvent removed under reduced pressure. Thepale yellow oil obtained was dissolved in 1,4-dioxane/water (1:1, 0.09Msolution) then NaHCO₃ (4 eq.) and Boc₂O (2 eq.) were added and themixture was stirred overnight at RT. The dioxane was removed underreduced pressure and the aqueous phase was extracted with EtOAc. Thecollected organic phases were washed with brine and dried (Na₂SO₄) andconcentrated under reduced pressure. The amber oil was purified bychromatography on silica gel eluting with EtOAc/petroleum ether (4:1) toobtain the title compound as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ:5.00 (1H, br. s), 4.30 (1H, br. s), 3.75 (3H, s), 2.21 (2H, t, J=7.4Hz), 1.70-1.80 (1H, m), 1.70-1.50 (3H, m), 1.45 (18H, s), 1.40-1.27 (4H,m). MS (ES) C₁₈H₃₃NO₆ requires: 359, found: 360 (M+H)⁺.

Step 3: (2S)-8-tert-Butoxy-2-[(tert-butoxycarbonyl)amino]-8-oxooctanoicacid (I3)

I2 was dissolved in a mixture of THF and H₂O (4:1, 0.35M solution) at RTand LiOH.H₂O (1.1 eq.) was added and the mixture was then stirred for1.5 hr. 1M HCl was added until pH 4-5, then the THF was removed underreduced pressure. The aqueous phase was extracted with EtOAc (3×); thecollected organic phases were washed with brine and then dried (Na₂SO₄).After removal of the solvent the title compound was obtained as acolorless oil which solidified upon standing, this was used in the nextstep without purification. ¹H NMR (400 MHz, CDCl₃) δ: 5.23 (1H, br. s),4.13 (1H, br. s), 2.21 (2H, t, J=7.4 Hz), 1.75-1.90 (1H, m), 1.70-1.50(3H, m), 1.45 (9H, s), 1.44 (9H, s), 1.50-1.25 (4H, m) MS (ES) C₁₇H₃₁NO₆requires: 345, found: 346 (M+H)⁺.

Step 4: tert-Butyl(7S)-7-[(tert-butoxycarbonyl)amino]-7-[5-(2-naphthyl)-1H-imidazol-2-yl]heptanoate(I4)

A solution of I3 and Cs₂CO₃ (0.5 eq) in EtOH (0.47M solution) wasstirred for 30 min at RT and then concentrated under reduced pressure.2-Bromo-1-(2-naphthyl)ethanone (1 eq.) was added to the resulting saltin DMF (0.27M solution) and the mixture was stirred for 1.5 hr at RTunder N₂. The DMF removed under reduced pressure, azeotroping withtoluene. EtOAc was added, the mixture was filtered and the residue waswashed with EtOAc. The combined filtrates were concentrated underreduced pressure. A solution of the resulting oil and NH₄OAc (20 eq.) inxylene was heated at reflux (150° C. bath temperature) for 2 hr. ExcessNH₄OAc and H₂O were removed using a Dean-Stark trap. The mixture wascooled to RT, diluted with EtOAc and washed with water (×2), sat. aq.NaHCO₃ solution, water (×2) and brine. The solution was dried (Na₂SO₄),concentrated under reduced pressure and the resulting brown oil waspurified by chromatography on silica gel eluting with EtOAc/petroleumether (9:1 to 1:1) to obtain the title compound as a colourless oil. ¹HNMR (300 MHz, CDCl₃) δ: 11.83 (1H, s), 8.24 (1H, s), 8.00-7.75 (4H, m),7.62 (1H, s), 7.53-7.35 (2H, m), 7.08 (1H, d, J=7.5 Hz), 4.55-4.70 (1H,m), 2.16 (2H, t, J=7.0 Hz), 1.95-1.65 (2H, m), 1.60-1.15 (6H, m), 1.40(9H, s), 1.38 (9H, s). MS (ES) C₂₉H₃₉N₃O₄ requires: 493, found: 494(M+H)⁺.

Step 5:2-[(1S)-1-Ammonio-6-carboxyhexyl]-5-(2-naphthyl)-1H-imidazol-1-iumbis(trifluoroacetate) (I5)

The foregoing compound I4 was dissolved in TFA/DCM (1:1) (0.2M solution)at 0° C. The cooling bath was removed and the mixture was stirred for 60min at RT. The solvents were removed under reduced pressure and theresidue was concentrated under reduced pressure, azeotroping withtoluene. The crude amino acid salt was used without furtherpurification. MS (ES) C₂₀H₂₃N₃O₂ requires: 337, found: 338 (M+H)⁺.

Step 6:2-((1S)-6-Carboxy-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}hexyl)-5-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate (I6)

A solution of EDC.HCl (1 eq.), HOBt (1 eq.) and(5-methoxy-2-methyl-1H-indol-3-yl)acetic acid (1 eq.) in DMF waspremixed at RT for 1 hr, and then this was added to a solution of 15 and^(i)PrNEt₂ (3 eq.) in DMF. The mixture was stirred for 3 hr at RT andafter this time the crude was directly purified by preparative RP-HPLC,using H₂O (0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18). Thedesired fractions were lyophilized to afford the titled compound as awhite fluffy powder.

¹H NMR (400 MHz, DMSO-d6) δ: 14.56 (1H, br. s), 12.00 (1H, br. s), 10.62(1H, s), 8.65 (1H, s), 8.33 (1H, s), 8.20-7.80 (6H, m), 7.59 (2H, s),7.10 (1H, d, J=7.68 Hz), 6.97 (1H, s), 6.60 (1H, s), 5.10-5.00 (1H, m),3.67 (3H, s), 3.65-3.40 (2H, m), 2.31 (3H, s), 2.16 (2H, br. s),2.05-1.95 (2H, m), 1.50-1.20 (6H, m). MS (ES) C₃₂H₃₄N₄O₄ requires: 538,found: 539 (M+H)⁺.

Example 1082-((1S)-7-(Hydroxyamino)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate (J1)

2-((1S)-6-Carboxy-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}hexyl)-5-(2-naphthyl)-1H-imidazolewas prepared as described in Example 107 step 6, Once the coupling wascompleted, to the coupling reaction solution were added EDC.HCl (1.5eq.) and HOBt (1.5 eq.) and after 1 h at RT hydroxylamine.HCl (1.5 eq)and DIPEA (1.5 eq.) were added. The mixture was stirred for overnight,then the crude was directly purified by preparative RP-HPLC, using H₂O(0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18). The desiredfractions were lyophilized to afford the titled compound as a whitepowder. ¹H NMR (400 MHz, DMSO-d6) δ: 14.44 (1H, br. s), 10.62 (1H, br.s), 10.31 (1H, s), 8.61 (1H, d, J=7.5 Hz), 8.33 (1H, s), 8.16 (1H, s),8.06 (1H, d, J=8.6 Hz), 8.01-7.86 (3H, m), 7.61 (2H, m), 7.10 (1H, d,J=8.6 Hz), 6.96 (1H, d, J=2.2 Hz), 6.59 (1H, dd, J=8.5, 2.2 Hz), 5.03(1H, m), 3.67 (3H, s), 3.65-3.40 (2H, m), 2.31 (3H, s), 2.03-1.85 (2H,m), 1.91 (2H, t, J=7.4 Hz), 1.50-1.20 (6H, m). MS (ES) C₃₂H₃₅N₅O₄requires: 553, found: 554 (M+H)⁺.

Procedure from Example Name (M + H)⁺ Example Number 1092-{(1S)-1-[(3-Fluoro-4-nitrobenzoyl)amino]-7- 453 1oxooctyl}-5-phenyl-1H-imidazol-1-ium trifluoroacetate 1102-Cyano-5-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol- 416 11-ium-2-yl)octyl]amino}carbonyl)pyridinium bis(trifluoroacetate) 1112-((1S)-1-{[(4-Cyanophenyl)sulfonyl]amino}-7- 501 2oxooctyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 1125-(2-Naphthyl)-2-((1S)-1-{[(3- 522 2nitrophenyl)sulfonyl]amino}-7-oxooctyl)-1H- imidazol-1-iumtrifluoroacetate 113 2-[(1S)-1-({[[2- 500 3(Dimethylammonio)ethyl](methyl)amino]sulfonyl}amino)-7-oxooctyl]-5-(2-naphthyl)-1H-imidazol-1- ium bis(trifluoroacetate) 1145-(2-Naphthyl)-2-{(1S)-7-oxo-1-[(1,3-thiazol-5- 447 1ylcarbonyl)amino]octyl}-1H-imidazol-1-ium trifluoroacetate 1155-(3-Chlorophenyl)-2-((1S)-1-{[(4- 485 2cyanophenyl)sulfonyl]amino}-7-oxooctyl)-1H- imidazol-1-iumtrifluoroacetate 116 5-(3-Chlorophenyl)-2-((1S)-1-{[(3- 507 2nitrophenyl)sulfonyl]amino}-7-oxooctyl)-1H- imidazol-1-iumtrifluoroacetate 117 2-((1S)-1-{[(4-Cyanophenyl)sulfonyl]amino}-7- 481 2oxooctyl)-5-(3-methoxyphenyl)-1H-imidazol-1-ium trifluoroacetate 1185-(3-Methoxyphenyl)-2-((1S)-1-{[(3- 501 2nitrophenyl)sulfonyl]amino}-7-oxooctyl)-1H- imidazol-1-iumtrifluoroacetate 119 5-(3-Methoxyphenyl)-2-{(1S)-7-oxo-1-[(1,3-thiazol-427 1 5-ylcarbonyl)amino]octyl}-1H-imidazol-1-ium trifluoroacetate 1202-((1S)-7-[(2-Aminophenyl)amino]-1-{[(5-methoxy- 630 1082-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 1215-(3-Methoxyphenyl)-2-[(1S)-1-({[(3S)-1- 427 1methylpyrrolidinium-3-yl]carbonyl}amino)-7- oxooctyl]-1H-imidazol-1-iumbis(trifluoroacetate) 122 (3S)-3-[({(1S)-1-[5-(3-Methoxyphenyl)-1H- 4411 imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]- 1-methylpiperidiniumbis(trifluoroacetate) 123(3S)-1-Isopropyl-3-[({(1S)-1-[5-(3-methoxyphenyl)- 469 11H-imidazol-1-ium-2-yl]-7- oxooctyl}amino)carbonyl]piperidiniumbis(trifluoroacetate) 124 5-(3-Chlorophenyl)-2-[(1S)-1-({[(3R)-1- 431 1methylpyrrolidinium-3-yl]carbonyl}amino)-7- oxooctyl]-1H-imidazol-1-iumbis(trifluoroacetate) 125 2-[(1S)-1-({[(3R)-1-Methylpyrrolidinium-3- 4471 yl]carbonyl}amino)-7-oxooctyl]-5-(2-naphthyl)-1H- imidazol-1-iumbis(trifluoroacetate) 1264-Methyl-2-[({(1S)-1-[5-(2-naphthyl)-1H-imidazol- 463 11-ium-2-yl]-7-oxooctyl}amino)carbonyl]morpholin- 4-iumbis(trifluoroacetate) 1274-[({(1S)-1-[5-(2-Naphthyl)-1H-imidazol-1-ium-2- 473 1yl]-7-oxooctyl}amino)carbonyl]-1- azoniabicyclo[2.2.2]octanebis(trifluoroacetate) 1284-[2-({(1S)-1-[5-(3-Chlorophenyl)-1H-imidazol-1- 461 1ium-2-yl]-7-oxooctyl}amino)-1-methyl-2- oxoethyl]morpholin-4-iumbis(trifluoroacetate) 129 2-[(1S)-1-{[(5-Methoxy-2-methyl-1H-indol-3-552 108 yl)acetyl]amino}-7-(methylamino)-7-oxoheptyl]-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 1305-(3-Methoxyphenyl)-2-[(1S)-1-({[(3R)-1- 427 1methylpyrrolidinium-3-yl]carbonyl}amino)-7- oxooctyl]-1H-imidazol-1-iumbis(trifluoroacetate) 131 (3R)-3-[({(1S)-1-[5-(3-Methoxyphenyl)-1H- 4411 imidazol-1-ium-2-yl]-7-oxooctyl}amino)carbonyl]- 1-methylpiperidiniumbis(trifluoroacetate) 132 5-(3-Chlorophenyl)-2-[(1S)-1-({[(3S)-1- 431 1methylpyrrolidinium-3-yl]carbonyl}amino)-7- oxooctyl]-1H-imidazol-1-iumbis(trifluoroacetate) 133 2-[(1S)-1-({[(3S)-1-Methylpyrrolidinium-3- 4471 yl]carbonyl}amino)-7-oxooctyl]-5-(2-naphthyl)-1H- imidazol-1-iumbis(trifluoroacetate) 134 2-((1S)-1-{[(5-Methoxy-2-methyl-1H-indol-3-501 1 yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H- imidazol-1-iumtrifluoroacetate 135 1-Methyl-4-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-425 1 1-ium-2-yl)nonyl]amino}carbonyl)piperidinium bis(trifluoroacetate)

Example 1362-(5-Methoxy-2-methyl-1H-indol-3-yl)-N-{(1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}acetamide(K5) Step 1:N′-(2S)-2-(tert-Butoxycarbonylamino]-8-hydroxydecanoyl-2-naphthohydrazide(K1)

Naphthyl-2-carboxylic acid, HOBt (1 eq.) and EDC.HCl (1 eq.) werestirred in DCM for 3 h, then(2S)-2-[(tert-butoxycarbonyl)amino]-8-hydroxydecanohydrazide (G2,Example 88, step 2) was added and the mixture was left stirring at RTfor 16 h. The mixture was partitioned between DCM and 0.1 M HCl. Theorganic phase separated, washed with sat aq. NaHCO₃ solution, dried(Na₂SO₄) and concentrated under reduced pressure. The crude product wasused without purification in the next step. MS (ES) C₂₆H₃₇N₃O₅ requires:471, found: 472 (M+H)⁺.

Step 2:N′-(2S)-2-[(tert-Butoxycarbonyl)amino]-8-oxodecanoyl-2-naphthohydrazide(K2)

The crude hydrazide (K1) was dissolved in anhydrous DCM and Dess-Martinperiodinane (1.5 eq.) was added and the mixture was stirred for 2 h atRT. Sat. aq. NaHCO₃ solution and 1M Na₂S₂O₃ aq. solution (6 eq.) wereadded and the mixture was stirred vigorously for 15 min. The phases wereseparated and the water phase was extracted with DCM. The combined DCMphases were dried (Na₂SO₄) and concentrated under reduced pressure. Theproduct was purified by preparative TLC using (SiO₂, EtOAc/Petroleumether (2:1) as eluent) to yield the product as a colourless oil. MS (ES)C₂₆H₃₅N₃O₅ requires: 469, found: 470 (M+H)⁺.

Step 3: tert-Butyl{(1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}-carbamate (K3)

A mixture of the hydrazide (K2),2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorinebound on polystyrene (2.3 mmol/g, 5 eq.) and TsCl (1.2 eq.) wassuspended in anhydrous THF. The suspension was gently stirred and heatedat 65° C. for 4 h. The mixture was filtered, and the resin was washedwith THF. The combined filtrates were concentrated under reducedpressure and the crude product was used in the next step withoutpurification. MS (ES) C₂₆H₃₃N₃O₄ requires: 451, found: 452 (M+H)⁺.

Step 4: (9S)-9-Amino-9-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]nonan-3-one(K4)

To a solution of the oxadiazole (K3) in DCM at 0° C. was added the samevolume TFA. The cooling bath was removed and the mixture was stirred for30 min at RT. The solvents were removed under reduced pressure and theresidue was partitioned between DCM and sat. aq. NaHCO₃ solution. Theorganic phase was dried (Na₂SO₄) and concentrated under reduced pressureand the crude product was used as such in the next step. MS (ES)C₂₁H₂₅N₃O₂ requires: 351, found: 352 (M+H)⁺.

Step 5:2-(5-Methoxy-2-methyl-1H-indol-3-yl)-N-{(1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}acetamide(K5)

To the crude amine (K4) was added a solution of(5-methoxy-2-methyl-1H-indol-3-yl)acetic acid (1.3 eq.), HOBt (1.3 eq.)and EDC.HCl (1.3 eq.) in DMF (premixed for 3 min), followed by DIPEA(1.3 eq.). The mixture was left stirring at RT for 3 h. The product wasisolated by preparative RP-HPLC, using H₂O (+0.1% TFA) and MeCN (+0.1%TFA) as eluents (column: C18). The acetonitrile was removed underreduced pressure from the desired fractions and the remaining waterphase was partitioned between sat aq. NaHCO₃ solution and DCM. The DCMphase was dried (Na₂SO₄) and concentrated under reduced pressure. Theresidue was then lyophilized from MeCN/H₂O to obtained the desiredproduct as a white solid. ¹H NMR (300 MHz, DMSO-d6) δ: 10.60 (1H, s),8.71 (1H, d, J=8.2 Hz), 8.47 (1H, s), 8.12-7.85 (4H, m), 7.65-7.45 (2H,m), 7.12-6.96 (2H, m), 6.62-6.50 (1H, m), 5.22-5.07 (1H, m), 3.65 (3H,s), 3.52 (2H, s), 2.42-2.23 (7H, m), 2.05-1.75 (2H, m), 1.47-1.15 (6H,m), 0.90 (3H, t, J=7.3 Hz). MS (ES) C₃₃H₃₆N₄O₄ requires: 552, found: 553(M+H)⁺. [α]_(D)=−13°, c=0.163 (EtOH)

Example 1372-(5-Methoxy-2-methyl-1H-indol-3-yl)-N-{(1S)-1-[5-(2-naphthyl)-1,3-oxazol-2-yl]-7-oxononyl}acetamide(L5) Step 1: 2-Azido-1-(2-naphthyl)ethanone (L1)

To 2-bromo-1-(2-naphthyl)ethanone in acetone was added NaN₃ (1 eq.) andthe mixture was stirred at RT for 24 h. EtOAc was added (10 vol.) andthe mixture was filtered. The filtrate was concentrated under reducedpressure and the residue was purified by flash chromatography on silicaeluting with 10% EtOAc/Petroleum ether to obtain the product as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ: 8.39 (1H, s), 8.02-7.82 (4H, m),7.69-7.50 (2H, m), 4.68 (2H, s). MS (ES) C₁₂H₉N₃O requires: 211, found:212 (M+H)⁺.

Step 2: 2-Amino-1-(2-naphthyl)ethanone.HCl (L2)

A solution of the azide (L1) in MeOH, was added 1 M HCl (1 eq.) and Pdon carbon (10% wt) and the mixture was stirred at RT under a H2atmosphere for 3.5 h. The catalyst was filtered off and washed withMeOH. The combined filtrate was concentrated under reduced pressure andthe crude material was used without purification in the next step. MS(ES) C₁₂H₁₁NO requires: 185, found: 186 (M+H)⁺.

Step 3: tert-Butyl[(1S)-1-({[2-oxo-(2-naphthyl)ethyl]amino}carbonyl)-7-oxononyl]-carbamate(L3)

A solution of (2S)-2-[(tert-butoxycarbonyl)amino]-8-oxodecanoic acid,EDC.HCl (1.3 eq.) and HOBt (1.3 eq.) in DMF was shaken for 5 min. To themixture was added a solution of crude amine (L2) (1 eq.) and DIPEA (1eq.) in DMF. The mixture was left to stir for 1 h. It was partitionedbetween DMF and 1 M NaOH. The DCM phase was washed sequentially with 1 MNaOH, 1 M HCl and brine, dried (Na₂SO₄) and concentrated under reducedpressure. The residue was purified by chromatography on silica using 50%EtOAc/Petroleum ether as eluent to yield the product was obtained as acolourless oil. MS (ES) C₂₇H₃₆N₂O₅ requires: 468, found: 469 (M+H)⁺.

Step 4: tert-Butyl{(1S)-1-[5-(2-naphthyl)-1,3-oxazol-2-yl]-7-oxononyl}-carbamate (L4)

PPh₃ and C₂Cl₆ (1 eq.) were dissolved in DCM at RT and Et₃N (2 eq.) wasadded, followed after 5 min. of stirring by dropwise addition of asolution of the amide (L3) (0.5 eq.) in DCM. The mixture was stirred for4 h at RT and was then poured into H₂O. The organic phase was separated,dried (Na₂SO₄) and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography on silica using 30%EtOAc/Petroleum ether as eluent to afford the product as a white solid.MS (ES) C₂₇H₃₄N₂O₄ requires: 450, found: 451 (M+H)⁺.

Step 5:2-(5-Methoxy-2-methyl-1H-indol-3-yl)-N-{(1S)-1-[5-(2-naphthyl)-1,3-oxazol-2-yl]-7-oxononyl}acetamide(L5)

The oxazoles (L4) (1 eq.) was dissolved in a mixture of DCM and TFA(1:1) and stirred at RT for 30 min, after which the solvents wereremoved under reduced pressure and the residue was partitioned betweenDCM and sat. aq. NaHCO₃ solution. The DCM phase was separated, dried(Na₂SO₄) and concentrated under reduced pressure. To the residue wasadded a solution of (5-methoxy-2-methyl-1H-indol-3-yl)acetic acid (1.3eq.), HOBt (1.3 eq.) and EDC.HCl (1.3 eq.) in DMF (premixed for 3 min),followed by DIPEA (1.3 eq.). The mixture was stirred at RT for 2 h andthen the desired product was isolated by preparative RP-HPLC, usingwater (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18). Thepooled product fractions were concentrated under reduced pressure andthe product was obtained as a white solid. ¹H NMR (300 MHz, DMSO-d6) δ:10.58 (1H, s), 8.58 (1H, d, J=8.2 Hz), 8.12 (1H, s), 8.05-7.85 (3H, m),7.85-7.72 (1H, m), 7.71 (1H, s), 7.60-7.44 (2H, m), 7.13-7.01 (2H, m),6.62-6.54 (1H, m), 5.10-4.93 (1H, m), 3.67 (3H, s), 3.51 (2H, s),2.42-2.20 (7H, m), 2.05-1.77 (2H, m), 1.47-1.15 (6H, m), 0.89 (3H, t,J=7.3 Hz). MS (ES) C₃₄H₃₇N₃O₄ requires: 551, found: 552 (M+H)⁺.

Example 1385-(1-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-2-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate (M7) Step 1:2,5-Dibromo-1-{[2-(dimethylsilyl)ethoxy]methyl}-1H-imidazole (M1)

To a stirred solution of 2,5-dibromo-1H-imidazole (1 eq.) in DMF at 0°C. under Ar was added NaH (1.2 eq.) and the mixture stirred for 30 minat 0° C. Then SEM-Cl (1.1 eq.) was added dropwise, and the mixturestirred 16 h warming to RT. The reaction was quenched by slow additionof H₂O and the desired product was extracted with EtOAc. The organiclayer was washed with brine, dried (Na₂SO₄) and concentrated underreduced pressure. The crude was purified by column chromatographyeluting with 10% EtOAc/Petroleum ether to afford the desired product. ¹HNMR (300 MHz, CD₃CN) δ: 7.10 (1H, s), 5.21 (2H, s), 3.53 (2H, t, J=7.3Hz), 0.90 (2H, t, J=7.3 Hz), 0.10 (9H, s). MS (ES) C₉H₁₆Br₂N₂OSirequires: 354:356:358 [1:2:1], found: 355:357:359 [1:2:1] (M+H)⁺.

Step 2:5-Bromo-2-(2-naphthyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole(M2)

To a stirred mixture of the imidazole (M1) (1 eq.) in toluene, 2 MNa₂CO₃ aq. solution (2 eq.) and 2-naphthylboronic acid (1 eq.) under Arwas added Pd(PPh₃)₄ (5 mol %) and the mixture heated at reflux 16 h.After cooling to RT, EtOAc was added and the mixture was washed with 2MNaOH. The organic layer was washed with brine, dried (Na₂SO₄) andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 10% EtOAc/Petroleum ether to afford thebromoimidazole. ¹H NMR (300 MHz, CD₃CN) δ: 8.28 (1H, s), 7.95-7.80 (4H,m), 7.58-7.48 (2H, m), 7.10 (1H, s), 5.20 (2H, s), 3.58-3.48 (2H, t,J=7.3 Hz), 0.95-0.85 (2H, t, J=7.3 Hz), 0.10 (9H, s). MS (ES)C₁₉H₂₃BrN₂OSi requires: 402:404 [1:1], found: 403:405 [1:1] (M+H)⁺.

Step 3: 5-(2-Ethyl-1,3-dioxolan-2-yl)hexanal (M3)

To a stirred mixture of5-(2-ethyl-1,3-dioxolan-2-yl)-N-methoxy-N-methyl-pentanamide (1 eq.)[Prepared by coupling 7-oxononanoic acid with N, O-dimethylhydroxylamineand subsequent ketal protection] in anhydrous THF at −78° C. was added a1 M LiAlH₄ solution in THF (1.6 eq.) slowly over 5 min. After 45 min thereaction was quenched by addition of Et₂O and then aq. Rochelle's saltsolution (10% w/v). The mixture was warmed to RT with a vigourousstirring. The organic phase was separated, washed with brine, dried(Na₂SO₄) and concentrated under reduced pressure. The residue waspurified by column chromatography eluting with 5% EtOAc/Petroleum etherto afford the desired aldehyde. ¹H NMR (300 MHz, CD₃CN) δ: 9.77 (1H, s),4.00 (4H, s), 2.44 (2H, t, J=7.0 Hz), 1.75-1.48 (6H, m), 1.46-1.25 (4H,m), 1.00-0.80 (3H, t, J=7.0 Hz).

Step 4:6-(2-Ethyl-1,3-dioxolan-2-yl)-1-(2-(2-naphthyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-5-yl)hexan-1-ol(M4)

To a stirred mixture of the bromoimidazole (M2) (1 eq.) in THF at −78°C. under Ar was added dropwise n-BuLi (1.2 eq., 1.6M solution inpentane). After 15 min a pre-cooled solution of the aldehyde (M3) (1.6eq.) in THF was added and the mixture was stirred at −78° C. for afurther 60 min. The reaction was quenched by slow addition of sat. aq.NH₄Cl solution and the desired product was then extracted with EtOAc.The organic layer was washed with brine, dried (Na₂SO₄) and concentratedunder reduced pressure. The crude material was purified by columnchromatography eluting with 5% EtOAc/Petroleum ether to afford thedesired alcohol. ¹H NMR (300 MHz, CD₃CN) δ: 8.30 (1H, s), 7.95-7.80 (4H,m), 7.58-7.48 (2H, m), 7.10 (1H, s), 5.30 (2H, s), 4.80-4.65 (1H, m),3.91 (4H, s), 2.52-2.35 (2H, m), 1.75-1.48 (6H, m), 1.46-1.25 (4H, m),1.10-0.80 (5H, m), 0.20-0.00 (9H, m). MS (ES) C₃₀H₄N₂O₄Si requires: 524,found: 525 (M+H)⁺.

Step 5:5-[1-Azido-6-(2-ethyl-1,3-dioxolan-2-yl)hexyl]-2-(2-naphthyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (M5)

The alcohol (M4) (1 eq.) was dissolved in toluene and DPPA (1.2 eq.) andthen DBU (1.2 eq.) were added and the mixture was heated with stirringat 50° C. overnight. After cooling to RT, EtOAc was added and themixture was washed with H₂O and then with 5% HCl solution. The organiclayer was washed with brine, dried (Na₂SO₄) and concentrated underreduced pressure. The residue was purified by column chromatographyeluting with 50% EtOAc/Petroleum ether to afford the desired azide. ¹HNMR (300 MHz, CDCl₃) δ: 8.30 (1H, s), 7.95-7.80 (4H, m), 7.58-7.48 (2H,m), 7.10 (1H, s), 5.32 (2H, s), 4.70-4.58 (1H, m), 3.90 (4H, s),3.69-3.59 (2H, m), 2.52-2.35 (2H, m), 1.75-1.48 (6H, m), 1.46-1.25 (4H,m), 1.00-0.80 (5H, m), 0.10 (9H, s). MS (ES) C₃₀H₄₃N₅O₃Si requires: 549,found: 550 (M+H)⁺.

Step 6:[6-(2-Ethyl-1,3-dioxolan-2-yl)-1-(2-(2-naphthyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-5-yl)hexyl]amine(M6)

The azide (M5) (1 eq.) was dissolved in EtOAc and stirred in thepresence of 10% Pd/C under an H2 atmosphere for 1 hr. The H2 atmosphereremoved and N₂ introduced. The reaction mixture was filtered and thecatalyst washed with MeOH and the filtrates concentrated under reducedpressure. The residue was purified by column chromatography eluting with70% EtOAc/Petroleum ether to afford the amine.

¹H NMR (300 MHz, CDCl₃) δ: δ: 8.42-8.35 (1H, s), 7.97-7.87 (2H, m),7.85-7.70 (2H, m), 7.58-7.45 (2H, m), 7.10 (1H, s), 5.37-5.25 (2H, s),4.70-4.58 (1H, m), 3.94-3.89 (4H, s), 3.69-3.59 (2H, m), 2.52-2.35 (2H,m), 1.75-1.48 (6H, m), 1.46-1.25 (4H, m), 1.00-0.80 (5H, m), 0.10 (9H,s). MS (ES) C₃₀H₄₅N₃O₃Si requires: 523, found: 524 (M+H)⁺.

Step 7:5-(1-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-2-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate (M7)

To a stirred solution of (5-methoxy-2-methyl-1-indol-3-yl)acetic acid(1.2 eq.), HOBt (1.2 eq.) and EDCI (1.2 eq.) in DCM was added the amine(M6). The mixture was stirred at RT for 16 hr. The reaction mixture waswashed successively with 0.25 M HCl solution, 0.25 M NaOH solution andbrine, dried (Na₂SO₄) and concentrated under reduced pressure. Theresulting amide was taken up in THF and a 1 M solution of TBAF (2 eq.)in THF was added and the mixture was heated at reflux for 6 h. Aftercooling to RT, EtOAc was added and the mixture was washed with H₂O andbrine, dried (Na₂SO₄) and concentrated under reduced pressure. Thedeprotected imidazole was then taken up in THF and 1 M HCl solution (4eq.) was added and the mixture was stirred at RT for 4 hr. The mixtureneutralized with 1 M NaOH and the ketone was extracted with EtOAc. Theorganics were washed with brine and concentrated under reduced pressure.The mixture was purified by preparative RP-HPLC, using H₂O (+0.1% TFA)and MeCN (+0.1% TFA) as eluents (column: C18). The desired fractionswere lyophilized to afford the titled compound as a colourless oil. ¹HNMR (300 MHz, d6-DMSO) δ: 10.70-10.60 (1H, s) 8.65-8.53 (1H, s),8.45-8.33 (1H, d, J=8 Hz), 8.25-8.12 (1H, d, J=8 Hz), 8.10-7.90 (3H, br,s), 7.75-7.65 (2H, m), 7.55 (1H, s), 7.23-7.13 (2H, d, J=8 Hz), 7.06(1H, s), 6.65 (1H, s), 5.05-4.95 (1H, m), 3.76 (3H, s), 3.53 (2H, s),2.45-2.30 (7H, m), 1.90-1.20 (8H, m), 0.93 (3H, t, J=7.3 Hz). MS (ES)C₃₁H₃₆N₂O₃S requires: 550, found: 551.

Example 1392-(5-Methoxy-2-methyl-1H-indol-3-yl)-N-[7-oxo-1-(2-phenyl-1,3-thiazol-5-yl)nonyl]acetamide(N4) Step 1:6-(2-Ethyl-1,3-dioxolan-2-yl)-1-(2-phenyl-1,3-thiazol-5-yl)hexan-1-one(N1)

To a stirred mixture of 2-(5-bromopentyl)-2-ethyl-1,3-dioxolane (1.6eq.) in anhydrous THF at −78° C. under Ar in the was added dropwise a1.6 M solution t-BuLi (3.2 eq.) in pentane. After 30 min a precooledsolution of N-methoxy-N-methyl-2-phenyl-1,3-thiazole-5-carboxamide (1eq., WO 2001052846) in THF was added and the mixture was stirred for 60min. at −78° C. and was then quenched by slow addition of sat. aq. NH₄Clsolution and the desired product was extracted with EtOAc. The organiclayer was washed with brine, dried (Na₂SO₄) and concentrated underreduced pressure. The crude was purified by column chromatographyeluting with 10% EtOAc/Petroleum ether to afford the desired alcohol. ¹HNMR (300 MHz, CD₃CN) δ: 8.76 (1H, s), 8.15-8.05 (2H, m), 7.70-7.52 (3H,m), 3.94-3.89 (4H, m), 3.02-2.91 (2H, t, J=8.0 Hz), 1.75-1.65 (4H, m),1.60-1.50 (4H, m), 1.45-1.30 (2H, m), 1.00-0.80 (3H, m). MS (ES)C₂₀H₂₅NO₃S requires: 359, found: 360 (M+H)⁺.

Step 2:6-(2-Ethyl-1,3-dioxolan-2-yl)-1-(2-phenyl-1,3-thiazol-5-yl)hexan-1-ol(N2)

To a stirred solution of the ketone (N1) in anhydrous EtOH at RT wasadded NaBH₄ (1 eq.) and the mixture stirred for 30 min. The reaction wasquenched by slow addition of sat. aq. NH₄Cl solution and the desiredproduct was extracted with EtOAc. The organic layer was washed withbrine, dried (Na₂SO₄) and concentrated under reduced pressure. The crudewas purified by column chromatography eluting with 10% EtOAc/Petroleumether to afford the desired alcohol. ¹H NMR (300 MHz, CD₃CN) δ: 7.95(2H, d, J=7.5 Hz), 7.65-7.45 (1H, s), 7.45-7.35 (3H, m), 5.05-4.95 (1H,m), 3.94-3.89 (4H, m), 1.75-1.55 (6H, m), 1.45-1.25 (6H, m), 1.00-0.80(3H, m). MS (ES) C₂₀H₂₇NO₃S requires: 361, found: 362 (M+H)⁺.

Step 3:[6-(2-Ethyl-1,3-dioxolan-2-yl)-1-(2-phenyl-1,3-thiazol-5-yl)hexyl]amine(N3)

5-[1-azido-6-(2-ethyl-1,3-dioxolan-2-yl)hexyl]-2-phenyl-1,3-thiazolefrom alcohol (N2) was prepared according to the procedure used inExample 89 Step 2. ¹H NMR (300 MHz, CDCl₃) δ: 8.00-7.90 (2H, d, J=7.5Hz), 7.57 (1H, s), 7.45-7.35 (3H, m), 5.10 (1H, t, J=7.3 Hz), 3.95 (4H,s), 1.89-1.78 (2H, m), 1.65-1.55 (4H, m), 1.45-1.25 (6H, m), 0.90-0.80(3H, m). MS (ES) C₂₀H₂₆N₄O₂S requires: 386, found: 387 (M+H)⁺. The azidewas then reduced according to the Example 89 Step 3 to afford thedesired amine (N3). ¹H NMR (300 MHz, CDCl₃) δ: 7.95 (2H, d, J=7.5 Hz),7.57 (1H, s), 7.45-7.35 (3H, m), 4.95 (1H, t, J=7.3 Hz), 3.95 (4H, s),1.89-1.78 (2H, m), 1.65-1.55 (4H, m), 1.45-1.25 (6H, m), 0.90-0.80 (3H,m). MS (ES) C₂₀H₂₈N₂O₂S requires: 360, found: 361 (M+H)⁺.

Step 4:2-(5-Methoxy-2-methyl-1H-indol-3-yl)-N-[7-oxo-1-(2-phenyl-1,3-thiazol-5-yl)nonyl]acetamide(N4)

This was prepared from amine (N3) according to the Example 89 Step 4. ¹HNMR (300 MHz, (CD₃)SO) δ: 10.65 (1H, s), 8.60-8.40 (1H, d, J=5 Hz),7.92-7.82 (2H, m) 7.66 (1H, s), 7.55-7.44 (3H, m), 7.10 (1H, d, J=8.6Hz), 7.05 (1H, s), 6.60 (1H, d, J=8.6 Hz), 5.17 (1H, app. q, J=6.0 Hz),3.76 (3H, s), 3.56-3.50 (2H, br. s), 2.45-2.30 (7H, m), 1.90-1.20 (8H,m), 0.93 (3H, t, J=7.3 Hz). MS (ES) C₃₀H₃₅N₃O₃S requires: 517, found:518.

Example 1402-((1S)-1-{[(1-Methylpiperidinium-4-yl)carbonyl]amino}-7-oxononyl)-4-phenylpyridiniumbis(trifluoroacetate) (O4) Step 1:N-[(1E)-6-(2-Ethyl-1,3-dioxolan-2-yl)hexylidene]-2-methylpropane-2-sulfinamide (O1)

A solution of 6-(2-ethyl-1,3-dioxolan-2-yl)hexanal (M3) (1.1 eq.),(R)-(+)-tert-butanesulfinamide (1.0 eq.) and anhydrous copper sulfate(2.2 eq.) in DCM was stirred for 70 h at RT. The reaction mixture wasfiltered through Celite. The solvent was removed under reduced pressure.The crude product was purified by flash chromatography with hexane/ethylacetate mixture as eluent to yield the desired product as an oil. ¹H NMR(300 MHz, CDCl₃) δ: 8.05 (1H, t, J=4.6 Hz), 3.91 (4H, s), 2.60-2.40 (2H,m), 1.70-1.50 (6H, m), 1.47-1.28 (4H, m), 1.18 (9H, s), 0.88 (3H, t,J=7.5 Hz). ¹³C NMR (75 MHz, CDCl₃) δ: 169.6, 111.9, 65.0, 56.5, 36.5,36.0, 29.8, 29.5, 25.5, 23.5, 22.3, 8.1. MS (ES) C₁₅H₂₉NO₃S requires:303, found: 304 (M+H)⁺.

Step 2:N-[(1S)-6-(2-Ethyl-1,3-dioxolan-2-yl)-1-(4-phenylpyridin-2-yl)hexyl]-2-methylpropane-2-sulfinamide(O2)

A solution of 2-bromo-4-phenylpyridine (1 eq.) in THF was cooled to −78°C. and treated dropwise with n-BuLi (1.1 eq.). After 30 min, a solutionof the imine (O1) (1.2 eq.) in THF was added. The reaction mixture wasstirred for 2 h at −78° C. and than slowly warmed to RT. The reactionwas quenched with H₂O and the aqueous phase was extracted with EtOAc.The combined organic phase was dried (MgSO₄) and solvent was removedunder reduced pressure. The crude amine was used without furtherpurification; LC-MS analysis shows two diastereomers 4.3:1. MS (ES)C₂₆H₃₈N₂O₃S requires: 459, found: 460 (M+H)⁺.

Step 3: (1S)-7-Oxo-1-(4-phenylpyridin-2-yl)nonan-1-aminiumtrifluoroacetate (O3)

The disubstituted pyridine (O2) (1 eq.) was dissolved in 1.25 N HCl inMeOH and was stirred for 30 min at RT. The reaction was quenched with 1NNaOH solution and was extracted with EtOAc. The organic phase was dried(MgSO₄) and the solvent was removed under reduced pressure. The crudeamine was used without further purification. A small portion waspurified by RP-HPLC and showed: ¹H NMR (300 MHz, d6-DMSO) δ: 8.68 (1H,d, J=5.1 Hz), 8.41 (3H, br. s), 7.87-7.74 (5H, m), 7.57-7.49 (2H, m),4.43 (1H, m), 2.39-2.31 (4H, m), 1.95-1.80 (2H, m), 1.45-1.13 (6H, m),0.86 (3H, t, J=4.6 Hz). MS (ES) C₂₀H₂₆N₂O requires: 310, found: 311(M+H)⁺.

Step 4:2-((1S)-1-{[(1-Methylpiperidinium-4-yl)carbonyl]amino}-7-oxononyl)-4-phenylpyridiniumbis(trifluoroacetate) (O4)

To a solution of the amine (O3) (1 eq.) and DIPEA (2.2 eq.) in DMF wasadded a solution of EDC.HCl (1.3 eq), HOBt (1.3 eq) and1-methylpiperidine-4-carboxylic acid (1.2 eq) in DMF. The mixture wasstirred at RT for 3 h and the desired material was isolated bypreparative RP-HPLC, using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) aseluents (C18 column). The desired fractions were lyophilized to affordthe imidazole as a colourless oil. ¹H NMR (300 MHz, CDCl₃) δ: 9.22 (1H,bs), 8.65 (1H, s), 8.05 (1H, s), 7.93-7.71 (4H, m), 7.66-7.53 (3H, m),5.17 (1H, m), 3.60 (1H, m), 3.44-3.13 (1H, m), 2.85-2.63 (5H, m),2.60-2.46 (1H, m), 2.43-2.33 (4H, m), 2.24-1.82 (6H, m), 1.61-1.25 (6H,m), 1.03 (3H, t, J=7.3 Hz). MS (ES) C₂₇H₃₇N₃O₂ requires: 436, found: 437(M+H)⁺.

Example 141(7S)-7-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]heptanoicacid (P4) Step 1:N′-(2)-8-tert-Butoxy-2-[(tert-Butoxycarbonyl)amino]-8-oxooctanyl-2-naphthohydrazide (P1)

A solution of EDC.HCl (1.5 eq.), HOBt (1.5 eq.) and(2S)-8-tert-Butoxy-2-[(tert-butoxycarbonyl)amino]-8-oxooctanoic acid(13, Example 107 Step 3) (1 eq.) in DMF (0.1 M) was premixed at RT for 1hr, and then 2-naphthohydrazide was added. The mixture was stirred for16 hr at RT and then concentrated to dryness under reduced pressure. Theresidue was dissolved in DCM, washed with 1 M HCl solution and brine.The solution was dried (Na₂SO₄), concentrated under reduced pressure andthe resulting brown oil was purified by chromatography on silica geleluting with 30% EtOAc/petroleum to obtain the hydrazide as a whitesolid. ¹H NMR (400 MHz, CDCl₃, 300 K)

9.36 (1H, broad s), 9.12 (1H, broad s), 8.36 (1H, s), 7.90-7.80 (4H, m),7.61-7.49 (2H, m), 5.15 (1H, d, J=8 Hz), 4.38-4.24 (1H, m), 2.20 (2H, t,J=7 Hz), 1.98-1.85 (1H, m), 1.76-1.64 (1H, m), 1.64-1.52 (2H, m),1.50-1.30 (22H, m). MS (ES) C₂₈H₃₉N₃O₆ requires: 513, found: 514 (M+H⁺).

Step 2: tert-Butyl(7S)-7-[(tert-butoxycarbonyl)amino]-7-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]heptanoate(P2)

The desired compound was prepared as a yellow solid from the hydrazide(P1) as described in Example 136 step 3. ¹H NMR (500 MHz, d6-DMSO, 325K) δ 8.57 (1H, s), 8.19-8.11 (2H, m), 8.09-8.00 (2H, m), 7.72-7.60 (2H,m), 7.58 (1H, broad s), 4.92-4.80 (1H, m), 2.18 (2H, t, J=7 Hz),2.00-1.80 (2H, m), 1.55-1.25 (24H, m). MS (ES) C₂₈H₃₇N₃O₅ requires: 495,found: 496 (M+H⁺).

Step 3:(1S)-6-Carboxy-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]hexan-1-aminiumtrifluoroacetate (P3)

The desired compound was prepared as a yellow solid from the carbamate(P2) as described in Example 136 step 4, however without the basic workup. ¹H NMR (300 MHz, d6-DMSO, 300 K)

12.0 (1H, broad s), 8.84 (3H, broad s), 8.65 (1H, s), 8.25-8.00 (4H, m),7.76-7.62 (2H, m), 4.94-4.84 (1H, m), 2.21 (2H, t, J=7 Hz), 2.15-1.95(2H, m), 1.60-1.25 (6H, m). MS (ES) C₁₉H₂₁N₃O₃ requires: 339, found: 340(M+H⁺).

Step 4:(7S)-7-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]heptanoicacid (P4)

The titled compound (P4) was obtained from the amine (P3) as describedin Example 136 step 5 to yield a white powder. ¹H NMR (300 MHz, d6-DMSO,300 K) δ 11.95 (1H, broad s), 10.59 (1H, broad s), 8.71 (1H, d, J=8 Hz),8.46 (1H, s), 8.14-7.90 (4H, m), 7.72-7.62 (2H, m), 7.10 (1H, d, J=8Hz), 7.04 (1H, d, J=2 Hz), 6.58 (1H, dd, J=8 Hz, J=2 Hz), 5.22-5.10 (1H,m), 3.64 (3H, s), 3.52 (2H, s), 2.33 (3H, s), 2.17 (2H, t, J=7 Hz),2.05-1.85 (2H, m), 1.50-1.20 (6H, m). MS (ES) C₃₁H₃₂N₄O₅ requires: 540,found: 541 (M+H⁺).

Example 142(7S)-7-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]heptanamide(O1)

(7S)-7-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]heptanoicacid was obtained as described in Example 141 step 4. Once the couplingwas complete, to the reaction mixture were added HATU (1.3 eq) and after30 min a solution of NH₃ in 1,4-dioxane (10 eq). The mixture was stirredfor overnight, then the crude was directly purified by preparativeRP-HPLC, using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (column:C18). The desired fractions were lyophilized to afford Q1 as a whitepowder. ¹H NMR (300 MHz, d6-DMSO, 300 K) δ 10.59 (1H, broad s), 8.71(1H, d, J=8 Hz), 8.46 (1H, s), 8.15-7.90 (4H, m), 7.72-7.60 (2H, m),7.18 (1H, broad s), 7.09 (1H, d, J=8 Hz), 7.03 (1H, d, J=2 Hz), 6.65(1H, broad s), 6.58 (1H, dd, J=8 Hz, J=2 Hz), 5.20-5.10 (1H, m), 3.64(3H, s), 3.52 (2H, s), 2.33 (3H, s), 2.00 (2H, t, J=7 Hz), 2.10-1.85(2H, m), 1.50-1.20 (6H, m). MS (ES) C₃₁H₃₃N₅O₄ requires: 539, found: 540(M+H⁺).

Example 143(7S)-7-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-[5-(2-naphthyl)-4H-1,2,4-triazol-3-yl]heptanoicacid (R4) Step 1:(2S)-8-tert-Butoxy-2-[(tert-Butoxycarbonyl)amino]-8-oxooctanohydrazide(R1)

The hydrazide (R1) was obtained as pale yellow oil from 8-tert-butyl1-methyl (2S)-2-[(tert-butoxycarbonyl)amino]octanedioate (12, Example107 Step 2) as described in Example 88 step 2. MS (ES) C₁₇H₃₃N₃O₅requires: 359, found: 360 (M+H)⁺.

Step 2: tert-butyl(7S)-7-[(tert-butoxycarbonyl)amino]-7-[5-(2-naphthyl)-4H-1,2,4-triazol-3-yl]heptanoate(R2)

The Desired Triazole was Prepared from the Hydrazide (R1) and2-Naphthonitrile as Described in Example 88 step 3 to yield a paleyellow oil. ¹H NMR (300 MHz, d6-DMSO, 340 K)

15.5 (1H, broad s), 8.82 (1H, s), 8.82 (1H, d, J=8 Hz), 8.05-7.84 (4H,m), 7.58-7.48 (2H, m), 5.55-5.40 (1H, m), 2.50-2.32 (1H, m), 2.28 (2H,t, J=7 Hz), 2.32-2.12 (1H, m), 1.80-1.30 (24H, m). MS (ES) C₂₈H₃₈N₄O₄requires: 494, found: 495 (M+H)⁺.

Step 3:(1S)-6-Carboxy-1-[5-(2-naphthyl)-4H-1,2,4-triazol-3-yl]hexan-1-aminiumtrifluoroacetate (R3)

The desired compound was prepared as a brown oil from the carbamate (R2)as described in Example 136 step 4, however without the basic work up.¹H NMR (300 MHz, d6-DMSO, 300 K)

14.78 (1H, broad s), 11.98 (1H, broad s), 8.58 (1H, s), 8.48 (3H, broads), 8.18-7.95 (4H, m), 7.68-7.55 (2H, m), 4.55-4.40 (1H, m), 2.20 (2H,t, J=7 Hz), 2.06-1.86 (2H, m), 1.60-1.20 (6H, m). MS (ES) C₁₉H₂₂N₄O₂requires: 338, found: 339 (M+H⁺).

Step 4:(7S)-7-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-[5-(2-naphthyl)-4H-1,2,4-triazol-3-yl]heptanoicacid (R4)

The titled compound (R4) was obtained from the amine (R3) as describedin Example 88 step 5 to yield a white powder. ¹H NMR (300 MHz, d6-DMSO,300 K) δ 10.57 (1H, broad s), 8.52 (1H, s), 8.39 (1H, d, J=8 Hz),8.15-7.90 (4H, m), 7.62-7.52 (2H, m), 7.09 (1H, d, J=9 Hz), 7.03 (1H, d,J=2 Hz), 6.59 (1H, dd, J=9 Hz, J=2 Hz), 5.07-4.95 (1H, m), 3.67 (3H, s),3.60-3.40 (2H, m), 2.32 (3H, s), 2.14 (2H, t, J=7 Hz), 1.97-1.77 (2H,m), 1.50-1.20 (6H, m). MS (ES) C₃₁H₃₃N₅O₄ requires: 539, found: 540(M+H⁺).

Example 144(7S)-7-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-[5-(2-naphthyl)-4H-1,2,4-triazol-3-yl]heptanamide(S1)

The titled compound (S1) was obtained from the amine (R3) as describedin Example 142 step 1 to yield a white powder. ¹H NMR (300 MHz, d6-DMSO,300 K) δ 10.57 (1H, broad s), 8.52 (1H, s), 8.39 (1H, d, J=8 Hz),8.14-7.91 (4H, m), 7.61-7.53 (2H, m), 7.17 (1H, broad s), 7.09 (1H, d,J=8 Hz), 7.02 (1H, d, J=2 Hz), 6.65 (1H, broad s), 6.59 (1H, dd, J=8 Hz,J=2 Hz), 5.07-4.95 (1H, m), 3.67 (3H, s), 3.60-3.40 (2H, m), 2.32 (3H,s), 1.98 (2H, t, J=7 Hz), 1.94-1.78 (2H, m), 1.50-1.20 (6H, m). MS (ES)C₃₁H₃₄N₆O₃ requires: 538, found: 539 (M+H⁺).

Example 1452-(5-Methoxy-2-methyl-1H-indol-3-yl)-N-{(1S)-1-[5-(2-naphthyl)-1,2,4-oxadiazol-3-yl]-7-oxononyl}acetamide(T7) Step 1: tert-Butyl [(1S)-1-(aminocarbonyl)-7-oxononyl]carbamate(T1)

To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-8-oxodecanoic acidin dioxane were added Py (1 eq.), Boc₂O (1.3 eq) and ammoniumbicarbonate (1.26 eq.). The reaction mixture was stirred at RT for 72hours and then the solvent was evaporated under reduced pressure. Theresulting crude was diluted with EtOAc and washed with H₂O, 1 N HCl andbrine. The organic phase was dried (Na₂SO₄) and concentrated underreduced pressure to yield a white powder which was as such in the nextstep. MS (ES) C₁₅H₂₈N₂O₄ requires: 300, found: 301 (M+H⁺).

Step 2: tert-Butyl [(1S)-1-cyano-7-oxononyl]carbamate (T2)

To a solution of the amide (T1) (1 eq.) and Et₃N (2.2 eq) in DCM at 0°C., TFAA (2 eq) was added dropwise. The reaction mixture was stirred atRT for 1 h, and then washed with sat. aq. NaHCO₃ solution, H₂O, brine.The organic phase was dried (Na₂SO₄) and concentrated under reducedpressure affording a yellow oil compound used as such in the next step.MS (ES) C₁₅H₂₆N₂O₃ requires: 282, found: 305 (M+Na⁺).

Step 3: tert-Butyl [(1S)-1-cyano-7-hydroxynonyl]carbamate (T3)

A solution of the nitrile (T2) (1 eq.) in MeOH was cooled to 0° C. andNaBH₄ (4 eq.) was added portionwise. The reaction mixture was stirred at0° C. for further 15 min and then at RT for 1 h. Then reaction wasquenched with water, the methanol was evaporated and the residueextracted with Et₂O (3×). The organic phases were collected, washed withbrine, dried (Na₂SO₄) and evaporated under reduced pressure. Theresulting crude was used directly in the next step. MS (ES) C₁₅H₂₈N₂O₃requires: 284, found: 307 (M+Na⁺).

Step 4: tert-Butyl{(1S)-7-hydroxy-1-[(hydroxyamino)(imino)methyl]nonyl}carbamate (T4)

A solution of NH₂OH.HCl (1.5 eq) in MeOH was added to a solution of KOH(1.5 eq) in MeOH. The mixture was stirred for 20 min, then the solid wasfiltered off and the resulting solution was added to the nitrile (T3) (1eq.). The mixture was then heated at refluxed, and after 16 hours thesolvent was removed under reduced pressure and the resulting crude wasused as such in the next step. MS (ES) C₁₅H₃₁N₃O₄ requires: 317, found:318 (M+H⁺).

Step 5: tert-Butyl{(1S)-7-hydroxy-1-[5-(2-naphthyl)-1,2,4-oxadiazol-3-yl]nonyl}carbamate(T5)

A mixture of 2-naphthoic acid (0.9 eq), TBTU (1 eq), HOBt (0.2 eq) andDIPEA (5 eq) in DMF was stirred at RT for 5 min; then added the aldoxime(T4) was added and the mixture was stirred for 1 h at RT. The mixturewas then warmed to 110° C. for 4 h. The solvent was removed underreduced pressure and the resulting crude used as such in the next step.MS (ES) C₂₆H₃₅N₃O₄ requires: 453, found: 454 (M+H⁺).

Step 6: tert-Butyl{(1S)-1-[5-(2-naphthyl)-1,2,4-oxadiazol-3-yl]-7-oxononyl}carbamate (T6)

To a solution of the oxadiazole (1 eq.) in DCM was added the Dess-Martinperiodinane (1.1 eq.). The mixture was stirred for 2 hr at RT and then asat. aq. NaHCO₃ (containing Na₂S₂O₃ (6 eq.)) was added and the mixturewas stirred for 15 min. The phases were separated and the H₂O phase wasextracted with DCM. The combined organic phases were dried (Na₂SO₄) andconcentrated under reduced pressure. The obtained product was used inthe next step without further purification. MS (ES) C₂₆H₃₃N₃O₄ requires:451, found: 452 (M+H⁺).

Step 7:2-(5-Methoxy-2-methyl-1H-indol-3-yl)-N-{(1S)-1-[5-(2-naphthyl)-1,2,4-oxadiazol-3-yl]-7-oxononyl}acetamide(T7)

The ketone (T6) (1 eq.) was dissolved in a mixture of DCM and TFA (1:1)and stirred at RT. After 20 min, the solvents were removed under reducedpressure and the residue was partitioned between DCM and sat. aq. NaHCO₃solution. The organic phase was separated, dried (Na₂SO₄) andconcentrated under reduced pressure.

To the residue was added a solution of(5-methoxy-2-methyl-1H-indol-3-yl)acetic acid (1.05 eq.), HOBt (1.05eq.) and EDC.HCl (1.05 eq.) in DCM (premixed for 3 min), followed byDIPEA (1.05 eq.). The mixture was left stirring at room temperature for4 hr. The product was isolated by preparative RP-HPLC, using water (0.1%TFA) and acetonitrile (0.1% TFA) as eluents (column: C18), the desiredfractions were lyophilized to afford the final product as a white fluffycompound. ¹H NMR (300 MHz, d6-DMSO) δ: 10.57 (1H, s), 8.75 (1H, s), 8.60(1H, d, J=8.2 Hz), 8.18-7.18 (4H, m), 7.65-7.49 (2H, m), 7.16-6.98 (2H,m), 6.63-6.54 (1H, m), 5.11-4.98 (1H, m), 3.68 (3H, s), 3.58-3.42 (2H,m), 2.42-2.22 (7H, m), 1.97-1.75 (2H, m), 1.50-1.12 (6H, m), 0.89 (3H,t, J=7.2 Hz). MS (ES) C₃₃H₃₆N₄O₄ requires: 552, found: 553 (M+H⁺).

Example 1462-(5-Methoxy-2-methyl-1H-indol-3-yl)-N-{(1S)-1-[3-(2-naphthyl)-1,2,4-oxadiazol-5-yl]-7-oxononyl}acetamide(U2) Step 1: tert-Butyl{(1S)-1-[3-(2-naphthyl)-1,2,4-oxadiazol-5-yl]-7-oxononyl}carbamate (U1)

A mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-8-oxodecanoic acid (1eq), TBTU (1.2 eq), HOBt (0.2 eq) and DIPEA (5 eq) in DMF was stirred atRT for 5 min; then added N-hydroxynaphthalene-2-carboximidamide wasadded and the mixture was stirred at RT for 20 min, after which time themixture was warmed to 110° C. for 2 h. The solvent was removed underreduced pressure and the resulting crude used as such in the next step.MS (ES) C₂₆H₃₃N₃O₄ requires: 451, found: 452 (M+H⁺).

Step 2:2-(5-Methoxy-2-methyl-1H-indol-3-yl)-N-{(1S)-1-[3-(2-naphthyl)-1,2,4-oxadiazol-5-yl]-7-oxononyl}acetamide(U2)

The oxadiazole was converted into titled compound by deprotection andcoupling as described in Example 145 step 7. ¹H NMR (400 MHz, d6-DMSO)δ: 10.60 (1H, s), 8.80 (1H, d, J=7.8 Hz), 8.58 (1H, s), 8.16-7.98 (4H,m), 7.68-7.60 (2H, m), 7.10 (1H, d, J=8.6 Hz), 7.05 (1H, d, J=2.5 Hz),6.60 (1H, dd, J₁=8.6 Hz, J₂=2.5 Hz), 5.18-5.10 (1H, m), 3.71 (3H, s),3.58-3.47 (2H, m), 2.41-2.30 (7H, m), 2.02-1.86 (2H, m), 1.46-1.17 (6H,m), 0.90 (3H, t, J=7.3 Hz). MS (ES) C₃₃H₃₆N₄O₄ requires: 552, found: 553(M+H⁺).

Example 1472-{(1S)-1-[(Methoxycarbonyl)amino]-7-oxononyl}-5-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate (V3) Step 1:tert-Butyl[(1S)-7-oxo-1-(5-(2-naphthyl)-1H-imidazol-2-yl)nonyl]carbamate(V1)

The product was obtained as a pale yellow solid from(2S)-2-[(tert-butoxycarbonyl)amino]-8-oxodecanoic acid and2-bromo-1-(2-naphthyl)ethanone following the procedure described fortert-butyl [(1S)-7-oxo-1-(5-phenyl-1H-imidazol-2-yl)octyl]carbamate fromExample 1, Step 2. ¹H NMR (300 MHz, d6-DMSO) δ: 12.30-11.70 (1H, m),8.30-8.07 (1H, m), 7.95-7.72 (4H, m), 7.62 (1H, s), 7.50-7.31 (2H, m),7.12-6.90 (1H, m), 4.70-4.50 (1H, m), 2.245-2.30 (4H, m), 1.92-1.65 (2H,m), 1.55-1.15 (15H, m), 0.89 (3H, t, J=7.1 Hz). MS (ES) C₂₇H₃₅N₃O₃requires: 449, found: 450 (M+H)⁺.

Step 2: (9S)-9-Amino-9-[5-(2-naphthyl)-1H-imidazol-2-yl]nonan-3-one (V2)

The carbamate (V1) (1 eq.) was dissolved in TFA/DCM (1:1) at 0° C. Thecooling bath was removed and the mixture was stirred for 60 min at RT.The solvents were removed under reduced pressure and the remaining oilwas partitioned between DCM and sat. aq. NaHCO₃ solution. The organicphase was dried (Na₂SO₄) and concentrated to dryness under reducedpressure. The obtained crude product was used without purification inthe next step. MS (ES) C₂₂H₂₇N₃O requires: 349, found: 350 (M+H)⁺.

Step 3:2-{(1S)-1-[(Methoxycarbonyl)amino]-7-oxononyl}-5-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate (V3)

To a solution of the amine (V2) and Et₃N (2.2 eq.) in DCM was addedmethyl chloridocarbonate (2.2 eq.). The reaction mixture was stirred atRT until consumption of the starting material. The product was isolatedby preparative RP-HPLC, using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) aseluents (column: C18). The desired fractions were lyophilized to affordthe titled compound as colourless oil. ¹H NMR (400 MHz, CD₃CN) δ: 8.37(1H, s), 8.03 (1H, d, J=8.7 Hz), 8.00-7.95 (2H, m), 7.81 (1H, dd, J₁=8.7Hz, J₂=1.8 Hz), 7.72-7.65 (2H, m), 7.64-7.58 (2H, m), 5.14-5.05 (1H, m),3.66 (3H, s), 2.46-2.38 (4H, m), 2.07-1.99 (2H, m), 1.59-1.28 (6H, m),0.98 (3H, t, J=7.2 Hz). MS (ES) C₂₄H₂₉N₃O₃ requires: 407, found: 408(M+H⁺).

Example 1482-((1S)-1-{[(Dimethylamino)carbonyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate (W1)

To a solution of the amine (V2) and Et₃N (2.2 eq.) in DCM was addeddimethylcarbamyl chloride (2.2 eq.). The reaction mixture was stirred atRT until consumption of the starting material. The product was isolatedby preparative RP-HPLC, using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) aseluents (column: C18). The desired fractions were lyophilized to affordthe titled compound as colourless oil. ¹H NMR (300 MHz, CD₃CN) δ:7.80-7.65 (5H, m), 7.56-7.44 (2H, m), 7.42-7.35 (2H, m), 7.33 (1H, s),5.37-5.24 (1H, m), 3.01 (6H, s), 2.46-2.32 (4H, m), 2.24-2.01 (2H, m),1.61-1.24 (6H, m), 0.97 (3H, t, J=7.4 Hz). MS (ES) C₂₅H₃₂N₄O₂ requires:407, found: 421 (M+H⁺).

Example 1493-Nitro-N-[7-oxo-1-(4-phenyl-2-furyl)octyl]benzenesulfonamide (X5) Step1: 1-(4-Phenyl-2-furyl)oct-7-en-1-ol (X1)

To a stirred mixture of Mg (2.5 eq.) in anhydrous THF under Ar was added12 (>5 mol %) and the mixture heated at reflux until the solution becamecolourless. Then 7-bromohept-1-ene (2.2 eq.) was added dropwise, andupon complete addition the mixture was heated at reflux for 2.5 hr. Theresulting Grignard reagent obtained was used immediately for the nextstep.

The resulting Grignard solution was added to a solution of4-phenyl-2-furaldehyde (1 eq.) in THF at 0° C. under Ar and the mixturewas stirred for 30 min. The reaction was quenched by slow addition ofsat. aq. NH₄Cl solution and the desired product was extracted withEtOAc. The organic layer was washed with brine, dried (Na₂SO₄) andconcentrated under reduced pressure. The crude was purified by columnchromatography eluting with 5% EtOAc/Petroleum ether to afford thedesired alcohol. ¹H NMR (300 MHz, CD₃Cl3) δ: 7.65 (2H, d, J=7.3 Hz),7.42 (2H, t, J=7.2 Hz), 7.25-7.15 (1H, m), 6.60 (1H, d, J=5.3 Hz), 6.30(1H, d, J=5.3 Hz), 5.87-5.75 (1H, m), 5.05-4.89 (2H, m), 4.75-4.65 (1H,m), 2.15-2.05 (2H, m), 1.87-1.75 (2H, m), 1.45-1.35 (6H, m). MS (ES)C₁₈H₂₂O₂ requires: 270 found: 271 (M+H)⁺.

Step 2: 1-(4-Phenyl-2-furyl)oct-7-en-1-yl azide (X2)

The alcohol (X1) (1 eq.) was dissolved in toluene, to give a solution of0.5 M, together with DPPA (1.2 eq.) and then DBU (1.2 eq.) was added andthe mixture was heated with stirring at 50° C. overnight. After coolingto RT, EtOAc was added and the mixture was washed with H₂O and then with5% HCl solution. The organic layer was washed with brine, dried (Na₂SO₄)and concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 10% EtOAc/Petroleum ether to affordthe azide. ¹H NMR (300 MHz, CD₃Cl3) δ: 7.65 (2H, d, J=7.3 Hz), 7.42 (2H,t, J=7.2 Hz), 7.25-7.15 (1H, m), 6.60 (1H, d, J=5.3 Hz), 6.30 (1H, d,J=5.3 Hz), 5.87-5.75 (1H, m), 5.05-4.89 (2H, m), 4.45-4.35 (1H, m),2.15-2.05 (2H, m), 1.87-1.75 (2H, m), 1.45-1.35 (6H, m). MS (ES)C₁₈H₂₁N₃O requires: 295 found: 296 (M+H)⁺.

Step 3: [1-(4-Phenyl-2-furyl)oct-7-en-1-yl]amine (X3)

The azide (X2) was dissolved in THF under Ar and PPh₃ (1.2 eq.) wasadded and the solution was stirred overnight at RT. Water was added andthe mixture was stirred other 24 hours, and then the solutionconcentrated under reduced pressure and the crude purified by SCXcartridge, washing first with MeOH and then eluting the desired aminewith methanolic ammonia solution, the desired fractions wereconcentrated under reduced pressure. ¹H NMR (300 MHz, CD₃Cl3) δ: 7.65(2H, d, J=7.3 Hz), 7.42 (2H, t, J=7.2 Hz), 7.25-7.15 (1H, m), 6.60 (1H,d, J=5.3 Hz), 6.30 (1H, d, J=5.3 Hz), 5.87-5.75 (1H, m), 5.05-4.89 (2H,m), 3.95-3.85 (1H, m), 2.15-2.05 (2H, m), 1.87-1.75 (2H, m), 1.45-1.35(6H, m). MS (ES) C₁₈H₂₃NO requires: 269 found: 270 (M+H)⁺.

Step 4: 3-Nitro-N-[1-(4-phenyl-2-furyl)oct-7-en-1-yl]benzenesulfonamide(X4)

To a stirred solution of the amine (X3) (1 eq.) in DCM was added3-nitrobenzenesulfonyl chloride (1.2 eq.) and the mixture was stirred atRT for 2 hr. The reaction mixture was washed successively with 0.25 MHCl solution, 0.25 M NaOH solution and brine, dried (Na₂SO₄) andconcentrated under reduced pressure. The mixture was purified by columnchromatography eluting with 50% EtOAc/Petroleum ether to afford thesulfonamide. ¹H NMR (300 MHz, d6-DMSO) δ: 8.70 (1H, d, J=7.3 Hz), 8.40(1H, s) 8.15-8.05 (2H, m), 7.60 (1H, t, J=7.2 Hz), 7.45-7.25 (4H, m),6.60 (1H, d, J=5.3 Hz), 6.30 (1H, d, J=5.3 Hz), 5.87-5.75 (1H, br, m),5.05-4.89 (2H, t, J=8.3 Hz), 4.45-4.35 (1H, m), 2.15-2.05 (2H, m),1.87-1.75 (2H, m), 1.45-1.35 (6H, m). MS (ES) C₂₄H₂₆N₂O₅S requires: 454found: 455 (M+H)⁺.

Step 5: 3-Nitro-N-[7-oxo-1-(4-phenyl-2-furyl)octyl]benzenesulfonamide(X5)

To a stirred mixture of DMF-H₂O (5:1) were added CuCl (1 eq.) and PdCl₂(0.1 eq.) under the mixture was stirred under an O₂ atmosphere for 1hour and then the sulfonamide (X3) (1 eq.) was added. The final solutionwas left stirring under an O₂ atmosphere at RT for 18 h. The solutionwas then concentrated under reduced pressure and the residue taken up inDCM, washed with sat. aq. NH₄Cl solution and brine. The organics weredried (Na₂SO₄) and concentrated under reduced pressure. The mixture waspurified by preparative RP-HPLC, using H₂O (+0.1% TFA) and MeCN (+0.1%TFA) as eluents (column: C18). The desired fractions were lyophilized toafford the titled compound. ¹H NMR (300 MHz, 6-DMSO) δ: 8.70 (1H, d,J=7.3 Hz), 8.40 (1H, s) 8.15-8.05 (2H, m), 7.65-7.55 (1H, t, J=7.2 Hz),7.45-7.25 (4H, m), 6.60 (1H, d, J=5.3 Hz), 6.30 (1H, d, J=5.3 Hz),4.45-4.35 (1H, m), 2.40 (2H, t, J=7.2 Hz), 2.15-2.05 (3H, s), 1.87-1.75(2H, m), 1.45-1.45 (6H, m). MS (ES) C₂₄H₂₆N₂O₆S requires: 470 found: 471(M+H)⁺.

Example 1502-((1M)-7-[(Ethylsulfonyl)amino]-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate (Y1)

To a solution of(7S)-7-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-[5-(2-naphthyl)-1H-imidazol-2-yl]heptanoicacid (Free base of Example 107) (1 eq.) in DCM (0.2 M solution) wasadded EDCI (1.5 eq.), DMAP (1.5 eq.) and, after one hour under stirringat RT, ethanesulfonamide (1.5 eq.). The mixture was stirred overnightthen the solvent removed under reduced pressure and crude purified bypreparative RP-HPLC, using H₂O (0.1% TFA) and MeCN (+0.1% TFA) aseluents (column: C18). The desired fractions were lyophilized to affordthe titled compound as a white powder. ¹H NMR (400 MHz, DMSO) δ: 14.44(1H, br. s), 11.51 (1H, s), 10.62 (1H, s), 8.60 (1H, d, J=6.6 Hz), 8.32(1H, s), 8.16 (1H, s), 8.06 (1H, d, J=8.7 Hz), 8.00-7.92 (2H, m), 7.88(1H, d, J=8.7 Hz) 7.66-7.54 (2H, m), 7.09 (1H, d, J=8.7 Hz), 6.96 (1H,s), 6.59 (1H, d, J=8.7 Hz), 5.08-5.00 (1H, m), 3.67 (3H, s), 3.54 (2H,app. quart.), 3.33 (2H, q, J=7.4 Hz), 2.31 (3H, s), 2.24 (2H, t, J=7.5Hz), 2.03-1.83 (2H, m), 1.53-1.12 (6H, m), 1.18 (3H, t, J=7.4 Hz). MS(ES) C₃₄H₃₉N₅O₅S requires: 629, found: 630 (M+H)⁺.

Example 1515-(2-Naphthyl)-2-((1S)-8,8,8-trifluoro-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-1H-imidazol-1-iumtrifluoroacetate (Z1)

To a solution of(7S)-7-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-[5-(2-naphthyl)-1H-imidazol-2-yl]heptanoicacid (Free base of Example 107) (1 eq.) in EtOH (0.5 M solution) wasadded Na₂CO₃ (1 eq.). The heterogeneous mixture was stirred 40 min at RTthen the solvent was removed under reduced pressure. DCM was added (0.14M solution), the mixture was cooled at 0° C. with an ice-bath then TFAA(6 eq.) was added followed by pyridine (8 eq.). After 40 min at the sametemperature some water was added and the product extracted with DCM. Thecollected organic phase were treated with brine and dried (Na₂SO₄) andafter removing the solvent under reduced pressure the crude was purifiedby preparative RP-HPLC, using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) aseluents (column: C18). The desired fractions were lyophilized to affordthe titled compound as a white powder as a mixture of the ketone andhydrated form ¹H NMR (500 MHz, pyridine) δ: 11.65-11.55 (0.5H, m),11.50-11.38 (0.5H, m), 9.21-9.12 (0.5H, m), 8.71-8.63 (2H, m), 8.30-8.10(1.5H, m), 8.00-7.79 (4.5H, m), 7.56-7.30 (4H, m), 7.09-6.97 (1H, m),5.76-5.62 (1H, m), 4.11-3.96 (1.5, m), 3.85-3.71 (2.5H, m) 2.71-2.58(1H, m), 2.55-2.41 (3.5H, m), 2.40-2.23 (2H, m), 2.21-2.03 (2H, m),2.10-1.79 (1.5H, m), 1.70-1.00 (6H, m). MS (ES) C₃₃H₃₃F₃N₄O₃ requires:590, found: 609 (M+H₂O+H)⁺.

Examples 152-298 were made according to the reaction schemes and theprocesses given in Example 14, 32, 33, 87-89, 107, 108 and 136 to 151.

Procedure from Example Name (M + H)⁺ Example Number 1523-Nitro-N-[7-oxo-1-(4-phenyl-1,3-thiazol-2- 488 149yl)octyl]benzenesulfonamide 1532-((1S)-7-Amino-1-{[(5-methoxy-2-methyl-1H- 538 325indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2- naphthyl)-1H-imidazol-1-iumtrifluoroacetate 154 2-((1S)-7-(Dimethylamino)-1-{[(5-methoxy-2- 566 108methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 1552-((1S)-7-(Isopropylamino)-1-{[(5-methoxy-2- 580 108methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 1562-((1S)-7-Anilino-1-{[(5-methoxy-2-methyl-1H- 614 108indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2- naphthyl)-1H-imidazol-1-iumtrifluoroacetate 157 2-((1S)-7-(Benzylamino)-1-{[(5-methoxy-2- 628 108methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 1582-{(1S)-1-{[(5-Methoxy-2-methyl-1H-indol-3- 616 108yl)acetyl]amino}-7-[(methylsulfonyl)amino]-7-oxoheptyl}-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 1591-Methyl-4-[({(1S)-1-[5-(2-naphthyl)-4H-1,2,4- 476 88 triazol-3-yl]-7-oxononyl}amino)carbonyl]piperidinium trifluoroacetate 160(3S)-1-Methyl-3-[({(1S)-1-[5-(2-naphthyl)-4H- 462 881,2,4-triazol-3-yl]-7- oxononyl}amino)carbonyl]pyrrolidiniumtrifluoroacetate 161 (3S)-1-Methyl-3-[({(1S)-1-[5-(2-naphthyl)-4H- 47688 1,2,4-triazol-3-yl]-7- oxononyl}amino)carbonyl]piperidiniumtrifluoroacetate 162 N-{(1S)-1-[5-(2-Naphthyl)-4H-1,2,4-triazol-3-yl]-462 88 7-oxononyl}-1,3-thiazole-5-carboxamide 1634-Cyano-N-{(1S)-1-[3-(2-naphthyl)-1H-1,2,4- 516 88triazol-5-yl]-7-oxononyl}benzenesulfonamide 1642-((1S)-7-[Methoxy(methyl)amino]-1-{[(5- 582 108methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 1651-Methyl-4-[({(1S)-7-(methylamino)-1-[5-(2- 476 108naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxoheptyl}amino)carbonyl]piperidinium bis(trifluoroacetate) 1664-[({(1S)-7-(Hydroxyamino)-1-[5-(2-naphthyl)-1H- 478 108imidazol-1-ium-2-yl]-7- oxoheptyl}amino)carbonyl]-1-methylpiperidiniumbis(trifluoroacetate) 167 2-{(1S)-6-Carboxy-1-[(1,3-thiazol-5- 449 107ylcarbonyl)amino]hexyl}-5-(2-naphthyl)-1H- imidazol-1-iumtrifluoroacetate 168 4-[({(1S)-7-[(2-Aminophenyl)amino]-1-[5-(2- 553 108naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxoheptyl}amino)carbonyl]-1-methylpiperidinium bis(trifluoroacetate) 1692-[(1S)-6-Carboxy-1-({[(3R)-1- 449 107methylpyrrolidinium-3-yl]carbonyl}amino)hexyl]-5-(2-naphthyl)-1H-imidazol-1-ium bis(trifluoroacetate) 1702-[(1S)-6-Carboxy-1-({[(3S)-1- 449 107methylpyrrolidinium-3-yl]carbonyl}amino)hexyl]-5-(2-naphthyl)-1H-imidazol-1-ium bis(trifluoroacetate) 1712-((1S)-6-Carboxy-1- 445 326{[(dimethylamino)sulfonyl]amino}hexyl)-5-(2- naphthyl)-1H-imidazol-1-iumtrifluoroacetate 172 4-[({(1S)-7-[Methoxy(methyl)amino]-1-[5-(2- 506 108naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxoheptyl}amino)carbonyl]-1-methylpiperidinium bis(trifluoroacetate) 1732-((1S)-1-{[(5-Methoxy-2-methyl-1H-indol-3- 670 150yl)acetyl]amino}-7-oxo-7-{[(trifluoromethyl)sulfonyl]amino}heptyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 1742-((1S)-7-(Ethylamino)-1-{[(5-methoxy-2-methyl- 566 1081H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 175(3S)-3-[({(1S)-1-[3-(3,5-Dichlorophenyl)-1H-1,2,4- 480 88triazol-5-yl]-7-oxononyl}amino)carbonyl]-1- methylpyrrolidiniumtrifluoroacetate 176 4-[({(1S)-1-[3-(3,5-Dichlorophenyl)-1H-1,2,4- 50688 triazol-5-yl]-7-oxononyl}amino)carbonyl]-1-azoniabicyclo[2.2.2]octane trifluoroacetate 177N-{(1S)-1-[3-(3,5-Dichlorophenyl)-1H-1,2,4- 570 88triazol-5-yl]-7-oxononyl}-2-(5-methoxy-2-methyl- 1H-indol-3-yl)acetamide178 2-(5-Methoxy-2-methyl-1H-indol-3-yl)-N-{(1S)-1- 532 88[3-(3-methoxyphenyl)-1H-1,2,4-triazol-5-yl]-7- oxononyl}acetamide 1792-(5-Methoxy-2-methyl-1H-indol-3-yl)-N-[7-oxo- 504 1491-(4-phenyl-1,3-thiazol-2-yl)octyl]acetamide 1802-((1S)-1-{[(5-Methoxy-2-methyl-1H-indol-3- 551 1yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H- imidazol-3-iumtrifluoroacetate 181 2-{(1S)-1-[(1H-indol-3-ylacetyl)amino]-7- 507 1oxononyl}-5-(2-naphthyl)-1H-imidazol-3-ium trifluoroacetate 1822-((1S)-1-{[(2-Methyl-1H-indol-3- 521 1yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H- imidazol-3-iumtrifluoroacetate 183 2-((1S)-1-{[(5-Methoxy-1H-indol-3- 537 1yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H- imidazol-3-iumtrifluoroacetate 184 2-((1S)-1-{[(5-Bromo-1H-indol-3- 587 1yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H- imidazol-3-iumtrifluoroacetate 185 2-((1S)-1-{[(5-Fluoro-1H-indol-3- 525 1yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H- imidazol-3-iumtrifluoroacetate 186 1-[2-({(1S)-1-[5-(2-Naphthyl)-1H-imidazol-3-ium-508 1 2-yl]-7-oxononyl}amino)-2-oxoethyl]-1H- benzimidazol-3-iumbis(trifluoroacetate) 187 2-((1S)-1-{[(7-Methoxy-1-benzofuran-2- 524 1yl)carbonyl]amino}-7-oxononyl)-5-(2-naphthyl)- 1H-imidazol-3-iumtrifluoroacetate 188 2-((1S)-1-{[(5-Methoxy-1H-indol-2- 523 1yl)carbonyl]amino}-7-oxononyl)-5-(2-naphthyl)- 1H-imidazol-3-iumtrifluoroacetate 189 2-((1S)-1-{[(5-Fluoro-1H-indol-2- 511 1yl)carbonyl]amino}-7-oxononyl)-5-(2-naphthyl)- 1H-imidazol-3-iumtrifluoroacetate 190 6-[2-({(1S)-1-[5-(2-Naphthyl)-1H-imidazol-3-ium-510 1 2-yl]-7-oxononyl}amino)-2-oxoethyl][1,2,4]triazolo[1,5-a]pyrimidin-4-ium bis(trifluoroacetate) 1915-(2-Naphthyl)-2-((1S)-7-oxo-1-{[(4-phenyl-1,3- 551 1thiazol-2-yl)acetyl]amino}nonyl)-1H-imidazol-3- ium trifluoroacetate 1922-((1S)-1-{[(5-Chloro-1-benzothien-3- 558 1yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H- imidazol-3-iumtrifluoroacetate 193 2-((1S)-1-{[(4-Chloro-1H-indol-3- 541 1yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H- imidazol-3-iumtrifluoroacetate 194 5-(2-Naphthyl)-2-((1S)-7-oxo-1-{[(2-oxo-1,3- 525 1benzoxazol-3(2H)-yl)acetyl]amino}nonyl)-1H- imidazol-3-iumtrifluoroacetate 195 2-((1S)-1-{[(5-Methoxy-2-oxo-2,3-dihydro-1H- 553 1indol-3-yl)acetyl]amino}-7-oxononyl)-5-(2- naphthyl)-1H-imidazol-3-iumtrifluoroacetate 196 2-((1S)-1-{[(6-Methoxy-2-oxo-2,3-dihydro-1H- 553 1indol-3-yl)acetyl]amino}-7-oxononyl)-5-(2- naphthyl)-1H-imidazol-3-iumtrifluoroacetate 197 2-Ethyl-1-[3-({(1S)-1-[5-(2-naphthyl)-1H-imidazol-550 1 3-ium-2-yl]-7-oxononyl}amino)-3-oxopropyl]-1H- benzimidazol-3-iumbis(trifluoroacetate) 198 5-(2-Naphthyl)-2-{(1S)-1-[(1- 518 1naphthylacetyl)amino]-7-oxononyl}-1H-imidazol- 3-ium trifluoroacetate199 5-(2-Naphthyl)-2-{(1S)-1-[(2- 518 1naphthylacetyl)amino]-7-oxononyl}-1H-imidazol- 3-ium trifluoroacetate200 5-(2-Naphthyl)-2-((1S)-7-oxo-1-{[(2- 536 1oxoquinazolin-1(2H)-yl)acetyl]amino}nonyl)-1H- imidazol-3-iumtrifluoroacetate 201 2-((1S)-1-{[(4-Methyl-1-oxophthalazin-2(1H)- 550 1yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H- imidazol-3-iumtrifluoroacetate 202 5-(2-Naphthyl)-2-{(1S)-7-oxo-1- 468 1[(phenylacetyl)amino]nonyl}-1H-imidazol-3-ium trifluoroacetate 2032-((1S)-1-{[(2,6-Dichlorophenyl)acetyl]amino}-7- 536 1oxononyl)-5-(2-naphthyl)-1H-imidazol-3-ium trifluoroacetate 2042-((1S)-1-{[(2,4-Dichlorophenyl)acetyl]amino}-7- 536 1oxononyl)-5-(2-naphthyl)-1H-imidazol-3-ium trifluoroacetate 2052-[(1S)-1-({[2-Fluoro-6- 554 1 (trifluoromethyl)phenyl]acetyl}amino)-7-oxononyl]-5-(2-naphthyl)-1H-imidazol-3-ium trifluoroacetate 2062-[(1S)-1-({[2-Fluoro-3- 554 1 (trifluoromethyl)phenyl]acetyl}amino)-7-oxononyl]-5-(2-naphthyl)-1H-imidazol-3-ium trifluoroacetate 2072-[(1S)-1-{[(5-methoxy-2-methyl-1H-indol-3- 621 150yl)acetyl]amino}-7-oxo-7-(1,3-thiazol-2-ylamino)heptyl]-5-(2-naphthyl)-1H-imidazol-3-ium trifluoroacetate 2082-[(1S)-1-{[(5-methoxy-2-methyl-1H-indol-3- 622 150yl)acetyl]amino}-7-oxo-7-(1,3,4-thiadiazol-2-ylamino)heptyl]-5-(2-naphthyl)-1H-imidazol-3-ium trifluoroacetate 2092-Methyl-1-[2-({(1S)-1-[5-(2-naphthyl)-1H- 522 1imidazol-1-ium-2-yl]-7-oxononyl}amino)-2-oxoethyl]-1H-benzimidazol-3-ium bis(trifluoroacetate) 2101-[2-({(1S)-1-[5-(2-Naphthyl)-1H-imidazol-1-ium- 576 12-yl]-7-oxononyl}amino)-2-oxoethyl]-2-(trifluoromethyl)-1H-benzimidazol-3-ium bis(trifluoroacetate) 2112-{(1S)-1-[(1H-Indazol-1-ylacetyl)amino]-7- 508 1oxononyl}-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 2123-[2-({(1S)-1-[5-(2-Naphthyl)-1H-imidazol-1-ium- 519 12-yl]-7-oxononyl}amino)-2-oxoethyl]quinolinium bis(trifluoroacetate) 2132-((1S)-1-{[(Dimethylamino)(oxo)acetyl]amino}-7- 449 1oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 2142-{(1S)-1-[(1,2-Benzisoxazol-3-ylacetyl)amino]-7- 509 1oxononyl}-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 2152-((1S)-1-{[(2-Methyl-1H-indol-1- 521 1yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H- imidazol-1-iumtrifluoroacetate 216 2-{(1S)-1-[(1H-1,2,3-Benzotriazol-1- 509 1ylacetyl)amino]-7-oxononyl}-5-(2-naphthyl)-1H- imidazol-1-iumtrifluoroacetate 217 2-((1S)-1-{[(5-Cyano-1H-indol-1-yl)acetyl]amino}-532 1 7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 2182-((1S)-1-{[(Dimethylammonio)acetyl]amino}-7- 436 1oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium bis(trifluoroacetate) 2191-Methyl-4-[({(1S)-1-[5-(2-naphthyl)-1H-imidazol- 475 1 1-ium-2-yl]-7-oxononyl}amino)carbonyl]piperidinium bis(trifluoroacetate) 2204-[({(1S)-1-[5-(2-Naphthyl)-1H-imidazol-1-ium-2- 487 1yl]-7-oxononyl}amino)carbonyl]-1- azoniabicyclo[2.2.2]octanebis(trifluoroacetate) 221 (7S)-7-{[(5-Methoxy-2-methyl-1H-indol-3- 553144 yl)acetyl]amino}-N-methyl-7-[5-(2-naphthyl)-4H-1,2,4-triazol-3-yl]heptanamide 2224-[({(1S)-1-[5-(2-Naphthyl)-1,3,4-oxadiazol-2-yl]- 489 1367-oxononyl}amino)carbonyl]-1- azoniabicyclo[2.2.2]octanetrifluoroacetate 223 2-Ethyl-1-[3-({(1S)-1-[5-(2-naphthyl)-1,3,4- 552136 oxadiazol-2-yl]-7-oxononyl}amino)-3-oxopropyl]-1H-benzimidazol-3-ium trifluoroacetate 2246-[2-({(1S)-1-[5-(2-Naphthyl)-1,3,4-oxadiazol-2- 512 136yl]-7-oxononyl}amino)-2- oxoethyl][1,2,4]triazolo[1,5-a]pyrimidin-3-iumtrifluoroacetate 225 1-Methyl-4-[({(1S)-1-[5-(2-naphthyl)-1,3,4- 477 136oxadiazol-2-yl]-7- oxononyl}amino)carbonyl]piperidinium trifluoroacetate226 (3R)-1-Methyl-3-[({(1S)-1-[5-(2-naphthyl)-1,3,4- 463 136oxadiazol-2-yl]-7- oxononyl}amino)carbonyl]pyrrolidiniumtrifluoroacetate 227 (4R)-4-[({(1S)-1-[5-(2-Naphthyl)-1H-imidazol-3- 5481 ium-2-yl]-7-oxononyl}amino)carbonyl]-2,3,4,9-tetrahydro-1H-beta-carbolin-2-ium bis(trifluoroacetate) 228(7S)-7-{[(5-Methoxy-2-methyl-1H-indol-3- 554 142yl)acetyl]amino}-N-methyl-7-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]heptanamide 2294-[({(1S)-6-Carboxy-1-[5-(2-naphthyl)-1,3,4- 465 141oxadiazol-2-yl]hexyl}amino)carbonyl]-1- methylpiperidiniumtrifluoroacetate 230 (7S)-7-[5-(2-Naphthyl)-1,3,4-oxadiazol-2-yl]-7- 451141 [(1,3-thiazol-4-ylcarbonyl)amino]heptanoic acid 2314-[({(1S)-1-[5-(2,3-Dihydro-1,4-benzodioxin-6-yl)- 483 11H-imidazol-3-ium-2-yl]-7- oxononyl}amino)carbonyl]-1-methylpiperidiniumbis(trifluoroacetate) 2322-(5-Methoxy-2-methyl-1H-indol-3-yl)-N-{(1S)-1- 552 33[4-(2-naphthyl)-1,3-oxazol-2-yl]-7- oxononyl}acetamide 2332-((1S)-7-(Methylamino)-7-oxo-1-{[(1-pyridin-2- 539 327ylpiperidin-3-yl)carbonyl]amino}heptyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 2342-[2-({(1S)-7-(Methylamino)-1-[5-(2-naphthyl)- 510 3271H-imidazol-1-ium-2-yl]-7-oxoheptyl}amino)-2-oxoethyl]-2,3-dihydro-1H-isoindolium bis(trifluoroacetate) 2352-{(1S)-7-(Methylamino)-7-oxo-1-[(piperidin-1- 476 327ylacetyl)amino]heptyl}-5-(2-naphthyl)-1H- imidazol-1-iumtrifluoroacetate 236 4-[({(1S)-7-(Methylamino)-1-[5-(2-naphthyl)-1H- 488327 imidazol-1-ium-2-yl]-7- oxoheptyl}amino)carbonyl]-1-azoniabicyclo[2.2.2]octane bis(trifluoroacetate) 2375-[({(1S)-7-(Methylamino)-1-[5-(2-naphthyl)-1H- 511 327imidazol-1-ium-2-yl]-7-oxoheptyl}amino)carbonyl]-1,2,3,4-tetrahydro-1,8- naphthyridin-1-iumbis(trifluoroacetate) 2382-((1S)-7-(Methylamino)-7-oxo-1-{[(5-pyrrolidin- 530 3271-yl-2H-tetrazol-2-yl)acetyl]amino}heptyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 2392-{(1S)-7-(Methylamino)-7-oxo-1-[(1,3-thiazol-5- 462 327ylcarbonyl)amino]heptyl}-5-(2-naphthyl)-1H- imidazol-1-iumtrifluoroacetate 240 2-((1S)-7-(Methylamino)-1-{[(4-methyl-1,2,3- 477327 thiadiazol-5-yl)carbonyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 2412-{(1S)-7-(Methylamino)-7-oxo-1-[(pyridin-3- 456 327ylcarbonyl)amino]heptyl}-5-(2-naphthyl)-1H- imidazol-1-iumtrifluoroacetate 242 2-{(1S)-7-(Methylamino)-7-oxo-1- 469 327[(phenylacetyl)amino]heptyl}-5-(2-naphthyl)-1H- imidazol-1-iumtrifluoroacetate 243 (7S)-7-({[(3S)-1-Methylpyrrolidin-3- 451 141yl]carbonyl}amino)-7-[5-(2-naphthyl)-1,3,4- oxadiazol-2-yl]heptanoicacid 244 (3S)-3-[({(1S)-6-Carboxy-1-[5-(2-naphthyl)-4H- 450 1431,2,4-triazol-3-yl]hexyl}amino)carbonyl]-1- methylpyrrolidiniumtrifluoroacetate 245 (3S)-3-[({(1S)-7-amino-1-[5-(2-naphthyl)-4H- 449144 1,2,4-triazol-3-yl]-7-oxoheptyl}amino)carbonyl]-1-methylpyrrolidinium trifluoroacetate 2464-[({(1S)-1-[5-(2,3-Dihydro-1,4-benzodioxin-5-yl)- 483 3041H-imidazol-3-ium-2-yl]-7- oxononyl}amino)carbonyl]-1-methylpiperidiniumbis(trifluoroacetate) 247 4-[({(1S)-1-[5-(1,3-Benzothiazol-2-yl)-1H- 482304 imidazol-3-ium-2-yl]-7-oxononyl}amino)carbonyl]-1-methylpiperidinium bis(trifluoroacetate) 2484-[({(1S)-1-[5-(1-Benzothien-2-yl)-1H-imidazol-3- 481 304ium-2-yl]-7-oxononyl}amino)carbonyl]-1- methylpiperidiniumbis(trifluoroacetate) 249 2-[(1S)-1-{[(Benzylamino)carbonyl]amino}-7-484 328 (methylamino)-7-oxoheptyl]-5-(2-naphthyl)-1H- imidazol-1-iumtrifluoroacetate 250 2-[(1S)-1-({[(4- 500 328Methoxyphenyl)amino]carbonyl}amino)-7-(methylamino)-7-oxoheptyl]-5-(2-naphthyl)-1H- imidazol-1-iumtrifluoroacetate 251 2-[(1S)-1-{[(Cyclopentylamino)carbonyl]amino}-7-462 328 (methylamino)-7-oxoheptyl]-5-(2-naphthyl)-1H- imidazol-1-iumtrifluoroacetate 252 2-((1S)-7-(Methylamino)-1-{[(3- 536 328nitrophenyl)sulfonyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 2532-[(1S)-1-{[(4-Cyanophenyl)sulfonyl]amino}-7- 516 328(methylamino)-7-oxoheptyl]-5-(2-naphthyl)-1H- imidazol-1-iumtrifluoroacetate 254 2-[(1S)-7-(Methylamino)-1-({[(3S)-1- 462 328methylpyrrolidinium-3-yl]carbonyl}amino)-7-oxoheptyl]-5-(2-naphthyl)-1H-imidazol-1-ium bis(trifluoroacetate) 2552-[(1S)-7-(Methylamino)-1-({[(3R)-1- 462 328methylpyrrolidinium-3-yl]carbonyl}amino)-7-oxoheptyl]-5-(2-naphthyl)-1H-imidazol-1-ium bis(trifluoroacetate) 2562-[(1S)-1-{[(Benzyloxy)carbonyl]amino}-7- 485 328(methylamino)-7-oxoheptyl]-5-(2-naphthyl)-1H- imidazol-1-iumtrifluoroacetate 257 1-Methyl-4-[({(1R)-1-[5-(2-naphthyl)-1H-imidazol-475 1 1-ium-2-yl]-7- oxononyl}amino)carbonyl]piperidiniumbis(trifluoroacetate) 258(3R)-3-[({(1S)-6-Carboxy-1-[5-(2-naphthyl)-1,3,4- 451 141oxadiazol-2-yl]hexyl}amino)carbonyl]-1- methylpyrrolidiniumtrifluoroacetate 259 5-Methoxy-N-{(1S)-7-(methylamino)-1-[5-(2- 526 142naphthyl)-1,3,4-oxadiazol-2-yl]-7-oxoheptyl}-1H- indole-2-carboxamide260 (7S)-7-{[(Benzylamino)carbonyl]amino}-N- 486 142methyl-7-[5-(2-naphthyl)-1,3,4-oxadiazol-2- yl]heptanamide 2612-((1R)-1-{[(5-Methoxy-2-methyl-1H-indol-3- 551 1yl)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H- imidazol-1-iumtrifluoroacetate 262 4-[({(1S)-1-[5-(4-Methoxyquinolin-2-yl)-1H- 506 1imidazol-3-ium-2-yl]-7-oxononyl}amino)carbonyl]- 1-methylpiperidiniumbis(trifluoroacetate) 263 3-[2-((1S)-1-{[(1-Methylpiperidinium-4- 476 1yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-1- ium-5-yl]quinoliniumtris(trifluoroacetate) 264 6-[2-((1S)-1-{[(1-Methylpiperidinium-4- 476 1yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-1- ium-5-yl]quinoliniumtris(trifluoroacetate) 2651-Methyl-4-({[(1S)-7-oxo-1-(5-quinolin-2-yl-1H- 476 1 imidazol-1-ium-2-yl)nonyl]amino}carbonyl)piperidinium bis(trifluoroacetate) 2664-({[(1S)-1-(5-Isoquinolin-3-yl-1H-imidazol-1- 476 1ium-2-yl)-7-oxononyl]amino}carbonyl)-1- methylpiperidiniumbis(trifluoroacetate) 2671-Methyl-N-{1-[2-(2-naphthyl)-1H-imidazol-5-yl]- 475 1387-oxononyl}piperidine-4-carboxamide 2681-Methyl-N-[7-oxo-1-(3-phenyl-1H-pyrazol-5- 425 89yl)nonyl]piperidine-4-carboxamide 2692-[(1S)-1-(Acetylamino)-7-oxononyl]-5-(2- 392 1naphthyl)-1H-imidazol-1-ium trifluoroacetate 2702-((1S)-1-{[(1,3-Dimethylpyrrolidinium-3- 475 1yl)carbonyl]amino}-7-oxononyl)-5-(2-naphthyl)- 1H-imidazol-1-iumbis(trifluoroacetate) 2714-[3-({(1S)-1-[5-(2-Naphthyl)-1H-imidazol-1-ium- 539 12-yl]-7-oxononyl}amino)-3- oxopropyl]thiomorpholin-4-ium 1,1-dioxidebis(trifluoroacetate) 272 5-(2-Naphthyl)-2-{(1S)-7-oxo-1- 446 302[(trifluoroacetyl)amino]nonyl}-1H-imidazol-1-ium trifluoroacetate 2732-((1S)-1-{[2-(Dimethylammonio)-2- 463 1methylpropanoyl]amino}-7-oxononyl)-5-(2- naphthyl)-1H-imidazol-1-iumbis(trifluoroacetate) 274 2-((1S)-1-{[(1-Methylazetidinium-3- 447 1yl)carbonyl]amino}-7-oxononyl)-5-(2-naphthyl)- 1H-imidazol-1-iumbis(trifluoroacetate) 275 2-[(1S)-1-{[3-(2-Ethyl-1H-benzimidazol-1- 551327 yl)propanoyl]amino}-7-(methylamino)-7-oxoheptyl]-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 2766-[2-({(1S)-7-(Methylamino)-1-[5-(2-naphthyl)- 511 3271H-imidazol-1-ium-2-yl]-7-oxoheptyl}amino)-2-oxoethyl][1,2,4]triazolo[1,5-a]pyrimidin-3-ium bis(trifluoroacetate) 2772-((1S)-7-(Methylamino)-7-oxo-1-{[(2- 537 327oxoquinazolin-1(2H)-yl)acetyl]amino}heptyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 2782-((1S)-7-(Methylamino)-7-oxo-1-{[(2-oxo-1,3- 526 327benzoxazol-3(2H)-yl)acetyl]amino}heptyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 2791-ethyl-3-[({(1S)-7-(methylamino)-1-[5-(2- 490 327naphthyl)-1H-imidazol-1-ium-2-yl]-7-oxoheptyl}amino)carbonyl]piperidinium bis(trifluoroacetate) 2802-((1S)-1-{[Methoxy(oxo)acetyl]amino}-7- 436 147oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 2812-((1S)-1-{[2-Methyl-2- 449 1(methylammonio)propanoyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium bis(trifluoroacetate) 2822-(5-Methoxy-2-methyl-1H-indol-3-yl)-N-[7-oxo- 501 891-(3-phenyl-1H-pyrazol-5-yl)nonyl]acetamide 2831-Methyl-4-({[(1S)-7-oxo-1-(5-quinolin-2-yl-1H- 476 1 imidazol-1-ium-2-yl)nonyl]amino}carbonyl)piperidinium dichloride 2841-Methyl-4-[({(1S)-1-[5-(2-naphthyl)-1H-imidazol- 504 1 1-ium-2-yl]-7-oxononyl}amino)(oxo)acetyl]piperazin-1-ium bis(trifluoroacetate) 2852-((1S)-1-{[Morpholin-4-yl(oxo)acetyl]amino}-7- 491 301oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 2862-((1S)-1-{[Amino(oxo)acetyl]amino}-7- 421 1oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 2872-((1S)-1-{[3-(Diethylammonio)propanoyl]amino}- 477 17-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium bis(trifluoroacetate) 2882-((1S)-1-{[3- 449 1 (Dimethylammonio)propanoyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium bis(trifluoroacetate) 2892-((1S)-1-{[(5-Cyano-1H-indol-3-yl)acetyl]amino}- 468 17-oxooctyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 2902-{(1S)-1-[(Carboxycarbonyl)amino]-7-oxononyl}- 422 3005-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 2912-{(1S)-1-[(Methylsulfonyl)amino]-7-oxononyl}-5- 428 2(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 2922-((1S)-1-{[(Dimethylamino)sulfonyl]amino}-7- 457 3oxononyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 2935-methoxy-2-methyl-3-(2-oxo-2-{[(1S)-7-oxo-1-(4- 512 140phenylpyridinium-2-yl)nonyl]amino}ethyl)-1H- indoliumbis(trifluoroacetate) 294 2-ethyl-1-(3-oxo-3-{[(1S)-7-oxo-1-(4- 511 140phenylpyridinium-2-yl)nonyl]amino}propyl)-1H- 3,1-benzimidazol-1-iumbis(trifluoroacetate) 295 1-Methyl-N-{(1S)-1-[5-(2-naphthyl)-1,3,4- 477308 oxadiazol-2-yl]-7-oxononyl}piperidine-4- carboxamide 2966-[2-((1S)-1-{[(1-Methylpiperidinium-4- 476 1yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-1- ium-5-yl]quinoliniumtrichloride 297 N-{(1S)-1-[5-(2-Naphthyl)-1,3,4-oxadiazol-2-yl]-7- 489308 oxononyl}quinuclidine-4-carboxamide 2984-Methoxy-2-[2-((1S)-1-{[(1-methylpiperidinium- 506 14-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-3- ium-5-yl]quinoliniumtrichloride

Particular intermediates of the present invention are given in Example299.

Example 299

Intermediate 1 2-[(1S)-1-Ammonio-6-carboxyhexyl]-5- 338 (M + H)⁺(2-naphthyl)-1H-imidazol-1-ium bis(trifluoroacetate) Intermediate 2(1S)-1-[3-(2-Naphthyl)-1H-1,2,4- 351 (M + H)⁺triazol-5-yl]-7-oxononan-1-aminium trifluoroacetate Intermediate 3tert-Butyl {(1S)-1-[5-(2-naphthyl)-1H- 448 (M + H)⁺imidazol-2-yl]-7-oxononyl}carbamate Intermediate 4(1S)-7-Oxo-1-(4-phenylpyridin-2- 311 (M + H)⁺ yl)nonan-1-aminiumtrifluoroacetate Intermediate 5 2-[(1S)-1-Ammonio-7-oxooctyl]-5-(2- 336(M + H)⁺ naphthyl)-1H-imidazol-3-ium bis(trifluoroacetate) Intermediate6 2-[(1S)-1-Ammonio-7-oxooctyl]-5- 286 (M + H)⁺ phenyl-1H-imidazol-3-iumbis(trifluoroacetate)

Example 3002-{(1S)-1-[(Carboxycarbonyl)amino]-7-oxononyl}-5-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate (AA1)

Methyl({(1S)-1-[5-(2-naphthyl)-1H-imidazol-2-yl]-7-oxononyl}amino)(oxo)acetate(Prepared as in example 147) was dissolved in THF and a solution ofLiOH.H₂O (1.05 eq.) in H₂O was added and the mixture was then stirredfor 1 hr at RT. The reaction was quenched with 1M HCl until pH 5 wasreached and then the THF was removed under reduced pressure. The aqueousphase was extracted with DCM (3×); the combined organic phases werewashed with brine and then dried (Na₂SO₄) and concentrated under reducedpressure. The resulting crude was purified by preparative RP-HPLC, usingH₂O (0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18). Thedesired fractions were lyophilized to afford the titled compound ascolorless oil. ¹H NMR (300 MHz, DMSO-d6) δ: 9.39 (1H, d, J=8.2 Hz), 8.30(1H, s), 8.11-7.85 (6H, m), 7.58-7.47 (2H, m), 6.88-6.18 (1H, bs),5.15-5.02 (1H, m), 2.45-2.36 (4H, m), 2.13-1.87 (2H, m), 1.55-1.41 (2H,m), 1.40-1.20 (4H, m), 0.90 (3H, t, J=7.3 Hz). MS (ES) C₂₄H₂₇N₃O₄requires: 421, found: 422 (M+H)⁺.

Example 3012-((1S)-1-{[Morpholin-4-yl(oxo)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate (BB1)

A solution of EDC-HCl (1.1 eq.), HOBt (1.1 eq.) and Example 300, AA1 (1eq.) in DMF was premixed at RT for 1 hr, and then this was added to asolution of morpholine (1 eq.) and ^(i)PrNEt₂ (1 eq.) in DMF. Themixture was stirred at RT and the crude was directly purified bypreparative RP-HPLC, using H₂O (0.1% TFA) and MeCN (+0.1% TFA) aseluents (column: C18). The desired fractions were lyophilized to affordthe titled compound as colorless oil. ¹H NMR (400 MHz, DMSO-d6) δ: 9.40(1H, bs), 8.31 (1H, s), 8.06-7.88 (2H, m), 7.97-7.88 (3H, m), 7.61-7.50(2H, m), 6.89-6.01 (1H, bs), 5.13-5.04 (1H, m), 3.65-3.58 (4H, m),3.54-3.48 (4H, m), 2.44-2.36 (4H, m), 2.05-1.89 (2H, m), 1.52-1.41 (2H,m), 1.40-1.21 (4H, m), 0.89 (3H, t, J=7.3 Hz). MS (ES) C₂₈H₃₄N₄O₄requires: 490, found: 491 (M+H)⁺.

Example 3025-(2-Naphthyl)-2-{(1S)-7-oxo-1-[(trifluoroacetyl)amino]nonyl}-1H-imidazol-1-iumtrifluoroacetate (CC1)

To a solution of Example 147, V2 and Et₃N (1 eq.) in DCM at 0° C. wasadded TFAA (1 eq.). The reaction mixture was stirred at RT for 1 hr.After removal of the solvent under reduced pressure the resulting crudewas purified by preparative RP-HPLC, using H₂O (0.1% TFA) and MeCN(+0.1% TFA) as eluents (column: C18). The desired fractions werelyophilized to afford the titled compound as colorless oil. ¹H NMR (400MHz, CD3CN) δ: 10.67 (1H, d, J=8.0 Hz), 8.42 (1H, s), 8.07-8.01 (1H, m),8.00-7.93 (2H, m), 7.88-7.81 (1H, m), 7.74 (1H, s), 7.67-7.58 (2H, m),5.49-5.39 (1H, m), 2.48-2.37 (4H, m), 2.26-2.18 (2H, m), 1.61-1.42 (3H,m), 1.41-1.29 (3H, m), 0.99 (3H, t, J=7.3 Hz). MS (ES) C₂₄H₂₆F₃N₃O₂requires: 445, found: 446 (M+H)⁺.

Example 3032-((1S)-1-{[(1-Methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-iumdichloride (DD3) Step 1: tert-Butyl3-[({(1S)-1-[5-(2-naphthyl)-1H-imidazol-2-yl]-7-oxononyl}amino)-carbonyl]azetidine-1-carboxylate(DD1)

1-(tert-Butoxycarbonyl)azetidine-3-carboxylic acid (1.2 eq.), EDC-HCl(1.45 eq.) and HOBt (1.4 eq.) were stirred for 5 min in DMF. Theresulting clear solution was added to Example 147,V2 and left stirringat RT for 1 hr. The mixture was diluted with DCM and washed withsaturated aqueous NaHCO₃ solution. The organic phase was separated,dried (Na₂SO₄) and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel, eluting with 1:1petroleum ether/EtOAc. The combined product fractions were concentratedunder reduced pressure and the title compound was obtained as acolourless oil. MS (ES) C₃₁H₄₀N₄O₄ requires: 532, found: 533 (M+H)⁺.

Step 2:N-{(1S)-1-[5-(2-Naphthyl)-1H-imidazol-2-yl]-7-oxononyl}azetidine-3-carboxamide(DD2)

DD1 was dissolved in a 1:1 mixture of DCM and TFA. The mixture wasstirred at RT for 20 min then diluted with DCM. The mixture wasneutralized with 1M NaOH solution, the organic phase was separated,washed with brine, dried (Na₂SO₄), filtered and concentrated to drynessunder reduced pressure. The crude title compound was obtained as acolourless oil. MS (ES) C₂₆H₃₂N₄O₂ requires: 432, found: 433 (M+H)⁺.

Step 3:2-((1S)-1-{[(1-Methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-iumdichloride (DD3)

DD2 was dissolved in MeOH and formaldehyde (15 eq., 37% aq. solution)was added and the mixture was stirred for 4 minutes. NaOAc (3.2 eq.) andNaBH₃(CN) (3.2 eq.) were added and the mixture was stirred for 25 min atRT. The mixture was diluted with DCM and washed with sat. aq. NaHCO₃solution (5×) and brine. The organic phase was dried (Na₂SO₄) andconcentrated under reduced pressure. The residue was purified bypreparative RP-HPLC, using H₂O (0.1% TFA) and MeCN (0.1% TFA) as eluents(column: C18). The desired fractions were concentrated under the reducedpressure in order to remove the MeCN and sat. aq. NaHCO₃ solution wasadded. The solution was extracted with DCM (2×) and the combined organicphases were concentrated under reduced pressure. The residue waslyophilized from 0.1 M aq. HCl/MeCN to yield the title compound as apale yellow oil. ¹H NMR (400 MHz, DMSO-d6) δ: 15.50-14.20 (2H, br, m),10.61 (0.6H, br. s), 10.09 (0.4H, br. s), 9.21-9.00 (1H, m), 8.59-8.44(1H, m), 8.17 (1H, s), 8.10-7.86 (4H, m), 7.68-7.50 (2H, m), 5.40-5.20(1H, m), 4.40-4.16 (2H, m), 4.15-4.03 (1H, m), 4.01-3.84 (1H, m),3.78-3.65 (1H, m), 2.86-2.71 (3H, m), 2.45-2.34 (4H, m), 2.11-1.83 (2H,m), 1.56-1.18 (6H, m), 0.90 (3H, t, J=7.3 Hz). MS (ES) C₂₇H₃₄N₄O₂requires: 446, found: 447 (M+H)⁺.

Example 3042-((1S)-1-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-[4-(1H-pyrazol-1-yl)phenyl]-1H-imidazol-3-iumtrifluoroacetate (EE7) Step 1:2,4-Dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (EE1)

NaH (60%, 1.2 eq) was added portionwise to a solution of2,4-dibromoimidazole (1 eq.) in THF at 0° C. After 1 hr, SEM-Cl (1.2eq.) was added and the mixture was stirred at RT for 12 hr. The reactionwas carefully quenched with H₂O and the aqueous phase was extracted withEtOAc (3×). The combined organic phase was dried (MgSO₄) andconcentrated under reduced pressure. Purification by flashchromatography on silica gel eluting with 5-33% EtOAc/pentane yieldedthe title compound as an oil. ¹H NMR (300 MHz, CDCl₃) δ: 7.09 (1H, s),5.22 (2H, s), 3.54 (2H, t, J=8.1 Hz), 0.92 (2H, t, J=8.1 Hz), 0.00 (9H,s). MS (ES) C₉H₁₆Br₂N₂OSi requires: 354/356/358, found: 355/357/359(M+H)⁺.

Step 2:(−)-(R)—N-[(1S)-1-(4-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-6-(2-ethyl-1,3-dioxolan-2-yl)hexyl]-2-methylpropane-2-sulfinamide(EE2)

To solution of EE1 (1 eq) in dry THF at 78° C. under an Ar atmospherewas slowly added a solution of n-BuLi (1.1 eq). After 30 min a solutionof Example 140, O1 in THF was added and the reaction mixture was stirredfor 3 hr at −78° C. and then slowly warmed to RT over 2 hr. The reactionwas carefully quenched with H₂O (25 mL) and the aqueous phase wasextracted with EtOAc (3×). The combined organic phase was dried (MgSO₄)and evaporated to dryness under reduced pressure. The analysis of thecrude by LC-MS showed a diastereomeric excess of 77%. Purification byflash chromatography on silica gel 1-25% EtOAc/pentane yielded twofractions, the first fraction was a mixture of diastereomers (37% de),while the second fraction was the desired the (R,S)-diastereomer (>95%de). [α]_(D) ^(25° C.)=−19.0 (c=2.05 in DCM). ¹H NMR (300 MHz, CDCl₃) δ:6.88 (1H, s), 5.39 (1H, d, J=11.0 Hz), 5.12 (1H, d, J=11.0 Hz), 4.49(1H, m), 3.91 (4H, s), 3.74 (1H, d, J=7.5 Hz), 3.50 (2H, t, J=8.3 Hz),2.06 (2H, m), 1.65-1.51 (6H, m), 1.36-1.19 (4H, m), 1.15 (9H, s), 0.90(5H, m), 0.00 (9H, s); MS (ES) C₂₄H₄₅BrN₃O₄SSi requires: 579/581, found:580/582 (M+H)⁺.

Step 3:(9S)-9-Amino-9-(4-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)nonan-3-one(EE3)

EE2 was dissolved in 1.2 M HCl in MeOH (ca. 12 eq.) and the mixture wasstirred for 30 min at RT and then quenched with sat. aq. NaHCO₃solution. The mixture was extracted with DCM (2×) and the combinedorganic phases were dried (Na₂SO₄), filtered and concentrated to drynessunder reduced pressure to yield the crude product as a colourless oil.MS (ES) C₁₈H₃₄BrN₃O₂Si requires: 433, found: 434 (M+H)⁺.

Step 4: tert-Butyl5-methoxy-3-(2-methoxy-2-oxoethyl)-2-methyl-1H-indole-1-carboxylate(EE4)

(5-Methoxy-2-methyl-1H-indol-3-yl)acetic acid was dissolved in dry MeOH,amberlyst 15 resin (2.8 parts in weight) was added and the mixture wasstirred overnight at RT. The mixture was centrifuged, the supernatantwas separated and concentrated to dryness under reduced pressure. Theresidue was dissolved in DCM and washed with sat. aq. NaHCO₃ solution,dried (Na₂SO₄) and concentrated to dryness under reduced pressure. Theresulting oil was dissolved in MeCN and DMAP (0.2 eq.) and Boc₂O (1.2eq.) were added and the mixture was stirred for 2 h at RT. The solventwas removed under reduced pressure and the residue was used in the nextstep without purification. MS (ES) C₁₈H₂₃NOs requires: 333, found: 334(M+H)⁺.

Step 5: [1-(tert-Butoxycarbonyl)-5-methoxy-2-methyl-1H-indol-3-yl]aceticacid (EE5)

EE4 was dissolved in THF/water mixture (1:1) and LiOH (3 eq.) was addedand the mixture was stirred for 2 hr. The mixture was acidified with 0.1M HCl and extracted with DCM. The organic phase was washed with brine,dried (Na₂SO₄), filtered and concentrated to dryness under reducedpressure to yield a white solid. ¹H NMR (300 MHz, DMSO-d6) δ: 12.29 (1H,s), 7.90 (1H, d, J=9.1 Hz), 6.99 (1H, d, J=2.4 Hz), 6.84 (1H, dd, J₁=2.4Hz, J₂=9.1 Hz), 3.77 (3H, s), 3.62 (2H, s), 2.46 (3H, s), 1.62 (9H, s).MS (ES) C₁₇H₂₁NO₅ requires: 319, found: 320 (M+H)⁺.

Step 6: tert-Butyl3-(2-{[(1S)-1-(4-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-7-oxononyl]amino}-2-oxoethyl)-5-methoxy-2-methyl-1H-indole-1-carboxylate(EE6)

EE5 (1.2 eq.), EDC.HCl (1.3 eq.) and HOBt (1.3 eq.) in DMF were shakenfor 5 min and this mixture and DIPEA (1 eq.) was added to EE3. Themixture was left stirring overnight and was then partitioned between DCMand sat. aq. NaHCO₃ solution. The organic phase was dried (Na₂SO₄),concentrated to dryness under reduced pressure and the residue waspurified by flash chromatography on silica gel, eluting with petroleumether/EtOAc, 3:1. The combined product fractions were concentrated underreduced pressure and the title compound was obtained as a colourlesssolid. ¹H NMR (300 MHz, CDCl₃) δ: 7.97 (1H, d, J=9.1 Hz), 6.89-6.80 (2H,m), 6.73 (1H, m), 5.99 (1H, d, J=8.85 Hz), 5.58 (1H, d, J=10.8 Hz),5.17-4.98 (2H, m), 3.78 (3H, s), 3.58-3.42 (4H, m), 2.46 (3H, s),2.41-2.21 (4H, m), 1.85-1.69 (2H, m), 1.67 (9H, s), 1.50-1.34 (2H, m),1.25-1.06 (4H, m), 1.01 (3H, t, J=7.5 Hz), 0.94-0.81 (2H, m), −0.02 (9H,s). MS (ES) C₃₅H₅₃BrN₄O₆Si requires: 734, found: 735 (M+H)⁺.

Step 7:2-((1S)-1-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-[4-(1H-pyrazol-1-yl)phenyl]-1H-imidazol-3-iumtrifluoroacetate (EE7)

EE6, [4-(1H-pyrazol-1-yl)phenyl]boronic acid (1.5 eq.),dicyclohexyl-(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.25 eq.),Pd(OAc)₂ (0.1 eq.) and K₃PO₄ (3 eq.) were placed in a chromacoll tubeand suspended in degassed n-BuOH. The air was replaced by an argonatmosphere and the closed tube was stirred and heated to 90° C. for 16hr. The mixture was diluted with DCM, washed with 120 and 1M NaOH, thendried (Na₂SO₄) and concentrated to dryness under reduced pressure. Theresidue was treated with 0.33 M TBAF in THF (3 eq.) and the mixture washeated at 70° C. for 5 hr. It was diluted with DCM and washed with H₂O(3×). After centrifugation for 3 min at 3000 rpm the water phase wasremoved and the organic phase was concentrated under reduced pressureand the residue was dissolved in DCM/TFA (1:1) and was stirred for 45min at RT. The solvents were removed under reduced pressure and theresidue was partitioned between DCM and sat. aq. NaHCO₃ solution. Aftercentrifugation for 3 min at 3000 rpm the aqueous phase was removed andthe residue was concentrated to dryness under reduced pressure. Thecrude deprotected product was purified by preparative RP-HPLC, using H₂O(0.1% TFA) and MeCN (0.1% TFA) as eluents (column: C18). The pooledproduct fractions were lyophilized and the title compound was obtainedas a white solid. ¹H NMR (300 MHz, CDCl₃) δ: 14.23 (1H, br. s), 10.62(1H, s), 8.59 (1H, d, J=2.2 Hz), 8.54 (1H, d, J=6.6 Hz), 8.06-7.94 (3H,m), 7.93-7.84 (2H, m), 7.79 (1H, s), 7.10 (1H, d, J=11.5 Hz), 7.00-6.95(1H, m), 6.64-6.56 (2H, m), 5.05-4.94 (1H, m), 3.69 (3H, s), 3.57 (1H,d, J=15.0 Hz), 3.48 (1H, d, J=15.0 Hz), 2.42-2.28 (7H, m), 2.01-1.79(2H, m), 1.47-1.12 (6H, m), 0.90 (3H, t, J=7.3 Hz). MS (ES) C₃₃H₃₈N₆O₃requires: 566, found: 567 (M+H)⁺.

Example 3055-(2-Methoxyquinolin-3-yl)-2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-3-iumbis(trifluoroacetate) (FF5) Step 1: tert-Butyl3-({[(1S)-1-(4-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-7-oxononyl]amino}carbonyl)azetidine-1-carboxylate(FF1)

1-(tert-Butoxycarbonyl)azetidine-3-carboxylic acid (1.2 eq.), EDC HCl(1.45 eq.) and HOBt (1.4 eq.) were stirred for 5 min in DMF. The clearsolution was added to Example 304, EE3 and left stirring for 1 hr at RT.The mixture was diluted with DCM and washed with sat. aq. NaHCO₃solution. The organic phase was separated, dried (Na₂SO₄) andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel, eluting with 55% EtOAc/petroleum ether, toyield the titled compound as a colourless oil. ¹H NMR (300 MHz, CDCl₃)δ: 6.87 (1H, s), 6.43 (1H, d, J=7.3 Hz), 5.54 (1H, d, J=10.6 Hz),5.19-5.01 (2H, m), 4.06-3.85 (4H, m), 3.57-3.42 (2H, m), 3.15-3.02 (1H,m), 2.44-2.28 (4H, m), 1.97-1.76 (2H, m), 1.58-1.45 (2H, m), 1.40 (9H,s), 1.33-1.14 (4H, m), 1.01 (3H, t, J=7.3 Hz), 0.96-0.81 (2H, m), −0.02(9H, s). MS (ES) C₂₇H₄₇BrN₄O₅Si requires: 616, found: 617 (M+H)⁺.

Step 2:N-[(1S)-1-(4-Bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-7-oxononyl]azetidine-3-carboxamide(FF2)

The carbamate (FF1) was dissolved in 20% TFA/DCM and after 20 mintoluene was added and the mixture was concentrated under reducedpressure. The residue was diluted with DCM and washed with sat. aq.NaHCO₃ solution. The aqueous phase was extracted with DCM and thecombined organics were dried (Na₂SO₄) and concentrated to dryness underreduced pressure to yield the amine as a colourless oil. MS (ES)C₂₂H₃₉BrN₄O₃Si requires: 516, found: 517 (M+H)⁺.

Step 3:N-[(1S)-1-(4-Bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-7-oxononyl]-1-methylazetidine-3-carboxamide(FF3)

The title compound was prepared according to the procedure in Example303, step 3 to yield the crude product which was used withoutpurification by preparative RP-HPLC. MS (ES) C₂₃H₄₁BrN₄O₃Si requires:530, found: 531 (M+H)⁺.

Step 4: (2-Methoxyquinolin-3-yl)boronic acid (FF4)

(2-Fluoroquinolin-3-yl)boronic acid was dissolved in 1.25M HCl in MeOHand stirred for 1 hr at RT. The mixture was quenched with sat. aq.NaHCO₃ solution and the mixture was extracted with DCM (3×). Theorganics were dried (Na₂SO₄) and concentrated under reduced pressure toyield the crude product as a pale yellow solid which was used in thenext step without further purification. MS (ES) C₁₀H₁₀BNO₃ requires:203, found: 204 (M+H)⁺.

Step 5:5-(2-Methoxyquinolin-3-yl)-2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-3-iumbis(trifluoroacetate) (FF5)

A mixture of the bromide (FF3) and the boronic acid (FF4) (1.5 eq.),dicyclohexyl-(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.25 eq.),Pd(OAc)₂ (0.1 eq.) and K₃PO₄ (3 eq.) in n-BuOH in a chromacoll tube wasdegassed. The air was replaced by an Ar atmosphere and the closed tubewas heated with stirring at 90° C. for 2 hr. The mixture was dilutedwith DCM, washed with sat. aq. NaHCO₃ solution, dried (Na₂SO₄) andconcentrated to dryness under reduced pressure. The residue wasdissolved in DCM/TFA (1:1) and the mixture was stirred for 5 hr at RT.Toluene was added and the mixture was concentrated under reducedpressure, the residue was diluted with DCM and washed with sat. aq.NaHCO₃ solution. The aqueous phase was extracted with DCM and theorganics were dried (Na₂SO₄), filtered and concentrated to dryness underreduced pressure. The residue was purified by preparative RP-HPLC, usingH₂O (0.1% TFA) and MeCN (0.1% TFA) as eluents (column: C18) and thedesired fractions were lyophilized to yield the title compound wasobtained as a colourless oil. ¹H NMR (400 MHz, DMSO-d6) δ: 9.78 (1H, br.s), 8.80 (1H, br. s), 8.70 (1H, s), 7.93 (1H, d, J=7.6 Hz), 7.81 (2H, d,J=8.1 Hz), 7.72-7.64 (1H, m), 7.51-7.44 (1H, m), 5.08-4.98 (1H, m),4.41-4.27 (1H, m), 4.26-4.17 (1H, m), 4.14 (3H, s), 4.13-4.04 (1H, m),3.97-3.87 (1H, m), 3.67-3.55 (1H, m), 2.81 (3H, s), 2.43-2.35 (4H, m),2.03-1.77 (2H, m), 1.52-1.41 (2H, m), 1.40-1.19 (4H, m), 0.89 (3H, t,J=7.2 Hz). MS (ES) C₂₇H₃₅N₅O₃ requires: 477, found: 478 (M+H)⁺.

Example 3062-((1S)-1-{[3-(Dimethylammonio)propanoyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-iumdichloride (GG1)

A solution of N,N-dimethyl-β-alanine hydrochloride (1.25 eq.), TBTU(1.25 eq.) and DIPEA (2.5 eq.) in DCM was added to Example 147, V2 andwas stirred at RT for 1 hr. The mixture was diluted with DCM and washedwith sat. aq. NaHCO₃ solution, the organic phase was dried (Na₂SO₄) andconcentrated to dryness under reduced pressure. The resulting residuewas dissolved in THF, polymer-bound tetralkylammonium carbonate (2.5mmol/g, 10 eq.) was added and the mixture was shaken for 12 hr. Afterfiltration of the polymer and evaporation of the solvent under reducedpressure the desired material was isolated by preparative RP-HPLC, usingH₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column). Thedesired fractions were concentrated under reduced pressure to remove theMeCN and sat. aq. NaHCO₃ solution was added. The aqueous phase wasextracted with DCM (2×) and the combined organic phases wereconcentrated under reduced pressure. The residue was lyophilized from0.1 M aq. HCl/MeCN to obtain the desired compound as a pale yellowhydroscopic solid. ¹H NMR (400 MHz, DMSO-d6) δ: 15.70-14.60 (1H, br. m),10.53 (1H, br. s), 9.09 (1H, d, J=6.4 Hz), 8.58 (1H, s), 8.19 (1H, s),8.07-7.90 (4H, m), 7.63-7.54 (2H, m), 5.19-5.10 (1H, m), 3.37-3.26 (2H,m), 2.94-2.73 (3H, m), 2.74 (6H, s), 2.44-2.36 (4H, m), 2.09-1.88 (2H,m), 1.51-1.21 (6H, m), 0.89 (3H, t, J=7.3 Hz). ¹³C NMR (100 MHz,DMSO-d6) δ: 211.3, 170.3, 149.5, 133.1, 133.0, 129.2, 128.4, 128.2,127.5, 127.3, 124.9, 124.7, 123.6, 115.6, 52.8, 46.8, 42.5, 41.7, 35.3,33.2, 30.1, 28.4, 25.4, 23.4, 8.1. MS (ES) C₂₇H₃₆N₄O₂ requires: 448,found: 449 (M+H)⁺.

Example 3074-Methoxy-2-[2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]quinoliniumtrichloride (HH7) Step 1: 2-Chloro-1-(4-methoxyquinolin-2-yl)ethanone(HH1)

To a solution of 4-methoxyquinoline-2-carboxylic acid and DMF (50 μL) inDCM at 0° C. was added dropwise oxalyl chloride (1.2 eq). The coolingbath was removed and the mixture was stirred for 2 hr at RT, then thesolvent was removed under reduced pressure. The residue was dissolved inTHF/MeCN (1:1) and cooled to 0° C., a pre-cooled solution (0° C.) ofTMSCHN₂ (1.2 eq) and Et₃N (1.2 eq) was added dropwise and the resultingmixture was stirred for 2 hr at 0° C. An excess of 2M HCl solution inEt₂O was added and the reaction was stirred for further hour at 0° C.and then partitioned between sat. aq. NaHCO₃ solution and DCM. Theorganic phase was separated, dried (Na₂SO₄), and concentrated underreduced pressure to afford a dark brown solid which was used as such inthe next step. ¹H NMR (300 MHz, CDCl₃) δ: 8.47 (1H, d, J=8.0 Hz), 8.09(1H, d, J=8.4 Hz), 7.81-7.73 (1H, m), 7.66-7.58 (1H, m), 7.51 (1H, s),5.31 (2H, s), 4.13 (3H, s). MS (ES) Cl₂H₁₀ClNO₂ requires: 235, found:236 (M+H)⁺.

Step 2: 2-(4-Methoxyquinolin-2-yl)-2-oxoethyl(2S)-2-[(tert-butoxycarbonyl)amino]-8-oxodecanoate (HH2)

A solution of (2S)-2-[(tert-butoxycarbonyl)amino]-8-oxodecanoic acid (1eq.) and Cs₂CO₃ (0.5 eq) in EtOH was stirred for 30 min at RT and thenconcentrated under reduced pressure. The resulting residue was dilutedin DMF and HH1 (1 eq.) was slowly added during a period of 15 min. Themixture was stirred for 1 h at RT and then the solvent was evaporatedunder reduced pressure. The resulting crude was purified bychromatography on silica gel eluting with 80% EtOAc/petroleum ether toobtain the product as orange oil. MS (ES) C₂₇H₃₆N₂O₇ requires: 500,found: 501 (M+H)⁺.

Step 3: tert-Butyl{(1S)-1-[5-(4-methoxyquinolin-2-yl)-1H-imidazol-2-yl]-7-oxononyl}carbamate(HH3)

A mixture of the ester (HH2) and NH₄OAc (20 eq) were suspended in xyleneand heated in a microwave oven at 160° C. for 180 sec. The mixture wasdiluted with DCM and washed with sat. aq. NaHCO₃ solution. The organicphase was dried (Na₂SO₄), filtered and concentrated under reducedpressure and the resulting brown oil was purified by chromatography onsilica gel eluting with 2.5% MeOH/DCM to obtain the imidazole as orangeoil. MS (ES) C₂₇H₃₆N₄O₄ requires: 480, found: 481 (M+H)⁺.

Step 4:(9S)-9-Amino-9-[5-(4-methoxyquinolin-2-yl)-1H-imidazol-2-yl]nonan-3-one(HH4)

The imidazole (HH3) was dissolved in TFA/DCM (1:1) and the mixture wasstirred for an hour at RT. The solvents were removed under reducedpressure and the residue was partitioned between sat. aq. NaHCO₃solution and DCM. The organic phase was separated, dried (Na₂SO₄) andconcentrated under reduced pressure to yield the amine which was usedwithout further purification. MS (ES) C₂₂H₂₈N₄O₂ requires: 380, found:381 (M+H)⁺.

Step 5: tert-Butyl3-[({(1S)-1-[5-(4-methoxyquinolin-2-yl)-1H-imidazol-2-yl]-7-oxononyl}amino)carbonyl]azetidine-1-carboxylate(HH5)

The amine (HH4) (1 eq.) was added to a clear solution of EDC-HCl (1.45eq), HOBt (1.41 eq) and 1-(tert-butoxycarbonyl)azetidine-3-carboxylicacid (1.24 eq) in DMF. The mixture was stirred at RT for 30 min and wasdiluted with DCM and washed with 1N NaOH solution (2×). The organicphase was dried (Na₂SO₄), filtered and concentrated under reducedpressure and the resulting crude was used without further purification.MS (ES) C₃₁H₄₁N₅O₅ requires: 563, found: 564 (M+H)⁺.

Step 6:N-{(1S)-1-[5-(4-methoxyquinolin-2-yl)-1H-imidazol-2-yl]-7-oxononyl}azetidine-3-carboxamide(HH6)

The amide (HH5) was dissolved in a mixture of DCM/TFA (1:1) and themixture was stirred at RT for 1 hr and was then diluted with DCM and thesolvents were removed under reduced pressure. The residue waspartitioned between sat. aq. NaHCO₃ solution and DCM, then separated andthe organic phase was dried (Na₂SO₄), filtered and concentrated underreduced pressure to afford the crude amine was used without furtherpurification. MS (ES) C₂₆H₃₃N₅O₃ requires: 463, found: 464 (M+H)⁺.

Step 7:4-Methoxy-2-[2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]quinoliniumtrichloride (HH7)

The amine (HH6) was dissolved in MeOH, formaldehyde (15 eq., 37% aq.solution) was added and the mixture was stirred for 4 min. NaOAc (3.2eq.) and NaBH₃(CN) (3.2 eq.) were added and the mixture was stirred for25 min at RT. The mixture was diluted with DCM and washed sat. aq.NaHCO₃ solution (5×) and brine. The organic phase was dried (Na₂SO₄) andconcentrated under reduced pressure. The residue was purified bypreparative RP-HPLC, using H₂O (0.1% TFA) and MeCN (0.1% TFA) as eluents(column: C18). After lyophilization of the pooled product fractions, theresulting TFA salt was dissolved in some drops of water and waspartitioned between sat. aq. NaHCO₃ solution and DCM; the aqueous phasewas extracted with DCM (2×) and the combined organic extracts were dried(Na₂SO₄) and concentrated under reduced pressure. The residue was thenlyophilized from 0.1N HCl (aq.) and MeCN to yield the title compound wasas a pale yellow hydroscopic solid. ¹H NMR (400 MHz, D₂O) δ: 8.39 (1H,d, J=8.3 Hz), 8.28 (1H, s), 8.12-8.01 (2H, m), 7.84-7.77 (1H, m), 7.59(1H, s), 5.14-5.08 (1H, m), 4.68-4.55 (1H, m), 4.54-4.46 (1H, m), 4.37(3H, s), 4.32-4.20 (1H, m), 4.18-4.09 (1H, m), 3.88-3.78 (1H, m),3.02-2.98 (3H, m), 2.59-2.50 (4H, m), 2.11-1.97 (2H, m), 1.63-1.53 (2H,m), 1.50-1.28 (4H, m), 0.97 (3H, t, J=7.3 Hz). MS (ES) C₂₇H₃₅N₅O₃requires: 477, found: 478 (M+H)⁺.

Example 308N-{(1S)-1-[5-(2-Naphthyl)-1,3,4-oxadiazol-2-yl]-5-oxoheptyl}quinuclidine-4-carboxamide(H2) Step 1: tert-Butyl((1S)-1-{[2-(2-naphthoyl)hydrazino]carbonyl}-7-oxononyl)carbamate (II1)

A solution of EDC.HCl (1.4 eq.), HOBt (1.4 eq.) and(2S)-2-[(tert-butoxycarbonyl)amino]-8-oxodecanoic acid in DMF (0.5 M)was premixed at RT for 10 min, and then a solution of 2-naphthohydrazide(1 eq) in DMF (1 M) was added. The mixture was stirred for 16 hr at RTand then it was diluted in DCM, washed with 0.1 M HCl solution andbrine. The solution was dried (Na₂SO₄), concentrated under reducedpressure and the crude product was purified by chromatography on silicagel eluting with 1% MeOH/DCM to obtain the desired hydrazide. ¹H NMR(300 MHz, CDCl₃, 300 K)

9.64 (1H, broad s), 9.44 (1H, broad s), 8.36 (1H, s), 7.86-7.81 (4H, m),7.57-7.46 (2H, m), 5.36 (1H, d, J=7 Hz), 4.39-4.36 (1H, m), 2.41-2.32(4H, m), 1.90-1.84 (1H, m), 1.72-1.66 (1H, m), 1.56-1.28 (15H, m), 1.02(3H, t, J=7.5 Hz). MS (ES) C₂₆H₃₅N₃O₅ required: 469, found: 470 (M+H⁺).

Step 2:N-{(1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]-5-oxoheptyl}quinuclidine-4-carboxamide(II2)

The hydrazide (II1) was converted to the corresponding oxadiazole andthe Boc-protecting group removed following procedures in Example 136,steps 3 and 4 then the resulting amine (1 eq) was treated withquinuclidine-4-carboxylic acid (2.7 eq), TBTU (3.2 eq) and DIPEA (6.3eq) in DMF and was stirred overnight at RT. The product was isolated bypreparative RP-HPLC, using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) aseluents (column: C18). The desired fractions were basified with a sat.aq. NaHCO₃ solution and extracted with EtOAc. The EtOAc phase was dried(Na₂SO₄) and concentrated under reduced pressure to obtain the desiredproduct as a white powder. ¹H NMR (400 MHz, DMSO-d6, 300 K) δ: 8.55 (1H,s), 8.16-8.13 (2H, m), 8.04-8.01 (3H, m), 7.69-6.63 (2H, m), 5.21-5.16(1H, m), 2.76 (6H, t, J=7.5 Hz), 2.43-2.38 (4H, m), 2.05-1.90 (2H, m),1.63 (6H, t, J=7.5 Hz), 1.51-1.23 (6H, m), 0.91 (3H, t, J=7.2 Hz). MS(ES) C₂₉H₃₆N₄O₃ required: 488, found: 489 (M+H)⁺.

Example 309N-{(1S)-1-[5-(4-Methoxyquinolin-2-yl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}-1-methylazetidine-3-carboxamide(JJ3) Step 1: 4-Methoxyquinoline-2-carbohydrazide (JJ1)

The methyl 4-methoxyquinoline-2-carboxylate (1 eq) was dissolved ini-PrOH (0.75 M) and then hydrazine monohydrate (10 eq) was added. Thereaction mixture was heated at 80° C. overnight and then the solvent wasevaporated under reduced pressure and the crude product was used in thenext step without purification. MS (ES) C₁₁H₁₁N₃O₂ required: 217, found:218 (M+H)⁺.

Step 2:(9S)-9-Amino-9-[5-(4-methoxyquinolin-2-yl)-1,3,4-oxadiazol-2-yl]nonan-3-one(JJ2)

The title compound was prepared as described in Example 308, steps 1 and2, starting from hydrazide (JJ1) and(2S)-2-[(tert-butoxycarbonyl)amino]-8-oxodecanoic acid and was obtainedas brown oil. ¹H NMR (300 MHz, CDCl₃, 300 K) δ: 8.23 (1H, d, J=8.2 Hz),8.15 (1H, d, J=8.4 Hz), 7.77 (1H, t, J=8.4 Hz), 7.68 (1H, s), 7.59 (1H,t, J=8.2 Hz), 4.36 (1H, t, J=7 Hz), 4.15 (3H, s), 2.43-2.36 (6H, m),2.16-1.88 (2H, m), 1.65-1.32 (6H, m), 1.03 (3H, t, J=7.3 Hz). MS (ES)C₂₁H₂₆N₄O₃ required: 382, found: 383 (M+H)⁺.

Step 3:N-{(1S)-1-[5-(4-Methoxyquinolin-2-yl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}-1-methylazetidine-3-carboxamide(JJ3)

The title compound was prepared as described in Example 303, steps 1-3,from crude amine (JJ2). The after preparative HPLC purification thedesired fractions were basified with a sat. aq. NaHCO₃ solution. Theaqueous phase was extracted with DCM, the organic phase was dried(Na₂SO₄) and concentrated under reduced pressure to obtain the desiredproduct as a white powder. ¹H NMR (400 MHz, DMSO-d6, 300 K) δ: 8.64 (1H,d, J=7.7 Hz), 8.21 (1H, d, J=8.1 Hz), 8.09 (1H, d, J=8.3 Hz), 7.87 (1H,t, J=7.2 Hz), 7.70 (2H, m), 5.22-5.20 (1H, m), 4.17 (3H, s), 3.50-3.00(5H, m), 2.43-2.37 (4H, m), 2.17 (3H, s), 2.00-1.80 (2H, m), 1.50-1-20(6H, m), 0.89 (3H, t, J=7.2 Hz). MS (ES) C₂₆H₃₃N₅O₄ required: 479,found: 480 (M+H)⁺.

Example 3105-(Hydroxymethyl)-2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-iumtrifluoroacetate (KK6) Step 1:4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-carbaldehyde(KK1)

To a stirred solution of4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole(See WO03/022274) (1 eq) in THF at 40° C. was added dropwise a solutionof BuLi (2 eq.) in hexanes and the mixture was stirred at 40° C. for afurther 30 min. DMF (4 eq.) was then added and the cooling bath wasremoved and the reaction mixture was allowed to warm to RT and stirredfor 30 min, after which time it was quenched by addition of a sat. aq.NH₄Cl solution. The organics were extracted with EtOAc (2×), washed withbrine, dried (Na₂SO₄) and concentrated under reduced pressure. Thematerial was purified by column chromatography on silica eluting with15% EtOAc/petroleum ether. ¹H NMR (300 MHz, CDCl₃) δ: 9.81 (1H, s), 7.30(1H, s), 5.95 (2H, s), 4.87, (2H, s), 3.58 (2H, t, J=7.7 Hz), 1.05-0.85(20H, m), 0.05 (6H, s).

Step 2:1-(4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-6-(2-ethyl-1,3-dioxolan-2-yl)hexan-1-ol(KK2)

To a stirred solution of the 2-ethyl-2-(5-iodopentyl)-1,3-dioxolane (1.5eq) in Et₂O at −78° C. was added dropwise a solution of tert-BuLi (3eq.) in hexanes and the mixture was stirred at −40° C. for a further 30min. A solution of the aldehyde (KK1) (1 eq.) in Et₂O was added in oneportion and then after 5 min the cooling bath was removed and thereaction was allowed to warm to RT and stirred at RT for 1 hour. Thereaction was quenched by addition of a sat. aq. NH₄Cl solution andseparated. The aqueous layer was extracted with EtOAc (2×), then thecombined organic fractions were washed with brine, dried (Na₂SO₄) andconcentrated under reduced pressure. The material was purified by columnchromatography on silica eluting with 50-70% EtOAc/petroleum ether. ¹HNMR (300 MHz, CDCl₃) δ: 6.85 (1H, s), 5.45 (1H, d, J=10.0 Hz), 5.38 (1H,d, J=10.0 Hz), 4.82-4.65 (4H, m), 3.98-3.85 (4H, m), 3.55 (2H, t, J=7.7Hz), 2.00-1.88 (1H, m), 1.70-1.30 (1H, m), 0.97-0.82 (14H, m), 0.10-0.00(15H, s).

Step 3:1-(4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-6-(2-ethyl-1,3-dioxolan-2-yl)hexan-1-azide(KK3)

To a stirred solution of the substrate (KK2) (1 eq.) and DBU (1.5 eq) intoluene was added DPPA (1.5 eq) and the mixture was stirred at RT for 18hours. The mixture was diluted with Et₂O and washed with sat. aq. NaHCO₃solution and brine, then dried (Na₂SO₄) and concentrated under reducedpressure. The material was purified by column chromatography on silicaeluting with 25% EtOAc/petroleum ether.

¹H NMR (300 MHz, CDCl₃) δ: 6.91 (1H, s), 5.45 (1H, d, J=10.0 Hz), 5.39(1H, d, J=10.0 Hz), 4.72 (2H, s), 4.39 (1H, t, J=5.5 Hz), 3.95 (4H, app.s), 3.58 (2H, t, J=7.7 Hz), 2.22-2.05 (2H, m), 1.70-1.30 (10H, m),0.97-0.82 (14H, m), 0.10-0.00 (15H, s).

Step 4:N-[1-(4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-6-(2-ethyl-1,3-dioxolan-2-yl)hexyl]-2-(5-methoxy-2-methyl-1H-indol-3-yl)acetamide(KK4)

To a solution of the azide (KK3) (1 eq.) in THF was added PPh₃ (1.2 eq)and the mixture was stirred at RT for 60 hours, then H₂O (0.25 volumes)was added and the reaction was warmed at 45° C. for 24 hours. The THFwas removed under reduced pressure and then the organics were extractedwith EtOAc, washed with brine and concentrated under reduced pressure toyield1-(4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-6-(2-ethyl-1,3-dioxolan-2-yl)hexan-1-amine,MS (ES) C₂₇H₅₅N₃O₄Si₂ required: 541, found: 542 (M+H)⁺.

DMF was added to the crude mixture followed by(5-methoxy-2-methyl-1H-indol-3-yl)acetic acid (1.5 eq.), EDCI (1.5 eq.),HOBt (1.5 eq) and Et₃N (2.5 eq) and the mixture was stirred for 24hours. Xylene was added to the reaction and the mixture was concentratedunder reduced pressure. The residue was taken up in EtOAc and was washedwith sat. aq. NaHCO₃ solution and brine, then dried (Na₂SO₄) andconcentrated under reduced pressure. The mixture was purified by columnchromatography on silica eluting with 60-75% EtOAc/petroleum ether toyield the desired amide. ¹H NMR (400 MHz, CDCl₃) δ: 7.88 (1H, s), 7.16(1H, d, J=8.8 Hz), 6.85 (1H, d, J=1.5 Hz), 6.80 (2H, m), 5.60 (1H, d,J=10.4 Hz), 5.32 (1H, d, J=10.4 Hz), 5.24 (1H, q, J=8.8 Hz), 4.69 (1H,d, J=12.8 Hz), 4.65 (1H, d, J=12.8 Hz), 3.98 (4H, app. s), 3.80 (3H, s),3.66-3.48 (4H, s), 2.31 (3H, s), 1.87-1.48 (8H, m), 1.30-1.10 (6H),0.97-0.82 (12H), 0.08-0.00 (15H, m). MS (ES) C₃₉H₆₆N₄O₆Si₂ required:742, found: 743 (M+H)⁺.

Step 5:N-{6-(2-Ethyl-1,3-dioxolan-2-yl)-1-[5-(hydroxymethyl)-1H-imidazol-2-yl]hexyl}-2-(5-methoxy-2-methyl-1H-indol-3-yl)acetamide(KK5)

The amide (KK4) was dissolved in THF and 1 M TBAF solution in THF (2.5eq.) was added. The mixture was heated at 65° C. overnight and then wasquenched by addition of H₂O and the product extracted in DCM. Theorganic phase were washed with brine and dried (Na₂SO₄) and concentratedunder reduced pressure to obtain the desired intermediate. MS (ES)C₂₇H₃₈N₄O₅ requires: 498, found: 499 (M+H)⁺.

Step 6:5-(Hydroxymethyl)-2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-iumtrifluoroacetate (KK6)

A solution of the alcohol (KK5) in THF was treated with 1M HCl solution(4 eq.) and was stirred at RT for 4 hr. The mixture neutralized with 1 MNaOH and concentrated under reduced pressure. The mixture was purifiedby preparative RP-HPLC, using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) aseluents (column: C18) and the desired fractions were lyophilized toafford the titled compound. ¹HNMR (300 MHz, CD₃CN) δ: 9.00-8.90 (1H, s),8.15-8.00 (1H, d, J=7.0 Hz), 7.28-7.18 (1H, d, J=7.0 Hz), 7.15-7.05 (1H,s), 7.00-6.90 (1H, s), 6.70 (1H, d, J=7.0 Hz), 5.16 (1H, q, J=7.0 Hz),4.55 (2H, s), 3.78 (3H, s), 3.67 (1H, d, J=10.0 Hz), 3.60 (1H, d, J=10.0Hz), 2.70-2.20 (7H, m), 1.90-1.20 (8H, m), 1.00-0.75 (3H, t J=7.0 Hz).MS (ES) C₂H₃₄N₄O₄ requires: 454, found: 455 (M+H)⁺.

Example 3114-{[2-(1-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]methyl}morpholin-4-iumbis(trifluoroacetate) (LL2) Step 1:N-[6-(2-Ethyl-1,3-dioxolan-2-yl)-1-(5-formyl-1H-imidazol-2-yl)hexyl]-2-(5-methoxy-2-methyl-1H-indol-3-yl)acetamide(LL1)

To a stirred solution of the alcohol Example 310, KK5 in DCM was addedMnO₂ (10 eq.) and the mixture was stirred at RT overnight, then filteredthrough celite. The solvent was removed under reduced pressure to obtainthe desired aldehyde. ¹H NMR (300 MHz, CDCl₃) δ: 9.85-9.70 (1H, s),8.05-7.90 (1H, s), 7.65-7.55 (1H, s), 7.15-7.05 (1H, d. J=6.8 Hz),7.85-7.68 (2H, m), 4.85-4.75 (1H, m), 3.95-3.85 (4H, s), 3.85-3.75 (3H,s), 3.55-3.40 (2H, m), 2.30 (3H, s), 1.90-1.20 (8H, m), 1.00-0.75 (7H,m). MS (ES) C₂₇H₃₆N₄O₅ requires: 496, found: 497 (M+H)⁺.

Step 2:4-{[2-(1-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]methyl}morpholin-4-iumbis(trifluoroacetate) (LL2)

The aldehyde (LL1) was taken up in MeOH and morpholine (2 eq.) was addedfollowed by AcOH (2 eq.) and NaBH₃(CN) (1 eq) and the mixture wasstirred at RT for 4 hr. The reaction was quenched by addition of sat.aq. NH₄Cl solution and the mixture was concentrated under reducedpressure. Sat. aq. NaHCO₃ solution was added and the product wasextracted with EtOAc, dried (Na₂SO₄) and concentrated under reducedpressure. The mixture was purified by preparative RP-HPLC, using H₂O(+0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18). The desiredfractions were collected, then allowed to stand in the acid solutionuntil the ketal protection was removed, finally the solution waslyophilized to afford to the titled compound. ¹H-NMR (300 MHz, CDCl₃) δ:9.35 (1H, d, J=3 Hz), 9.03 (1H, s), 7.18 (1H, d, J=7.3 Hz), 7.03 (1H,s), 6.65 (1H, d, J=7.3 Hz), 5.65-5.55 (1H, br. s), 5.10 (1H, q, J=6.5Hz), 4.10 (2H, s), 3.95-3.60 (1H, br. m), 2.95-2.60 (2H, m), 2.45-2.30(7H, m), 2.05-1.90 (1H, m), 1.85-1.65 (1H, m), 1.55-1.15 (6H, m), 1.05(3H, t, J=7.0 Hz). MS (ES) C₂₉H₄₁N₅O₄ requires: 523, found: 524 (M+H)⁺.

Example 3122-(1-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-1H-imidazol-1-iumtrifluoroacetate (MM1)

To a stirred solution of the aldehyde Example 311, LL1 in THF was addedPh₃P═CHCO₂CH₃ (6 eq.) portionwise and the resulting mixture was stirredat RT overnight. The reaction was quenched by addition of 0.1 M HClsolution and extracted in EtOAc. The organics were dried (Na₂SO₄) andconcentrated under reduced pressure. The crude was purified bypreparative RP-HPLC, using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) aseluents (column: C18). The desired fractions were collected, left tostand in the acid solution in order to remove the ketal protection andthen lyophilized to afford to the titled compound. ¹H-NMR (300 MHz,CD₃CN) δ: 9.00-8.90 (2H, m), 7.45-7.35 (1H, d, J=8.3 Hz), 7.25 (1H, s),7.12 (1H, d, J=7.3 Hz), 6.95 (1H, s), 6.70-6.55 (2H, m), 5.20 (1H, q,J=6.5 Hz), 3.95-3.65 (6H, m), 3.55-3.40 (2H, m), 2.45-2.20 (7H, m),1.95-1.80 (2H, m), 1.45-1.00 (6H, m), 0.95 (3H, t, J=7.0 Hz). MS (ES)C₂₈H₃₆N₄O₅ requires: 508, found: 509 (M+H)⁺.

Example 3135-(2-Carboxyethyl)-2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-iumtrifluoroacetate (NN1)

The unsaturated ester Example 312, MM1 was dissolved in anhydrous EtOAcand stirred in the presence of 10% Pd/C under an H₂ atmosphere for 1 hr.The H₂ atmosphere was removed and N₂ introduced. The reaction mixturewas filtered and the catalyst washed with EtOAc and the filtratesconcentrated under reduced pressure. The crude was purified bypreparative RP-HPLC, using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) aseluents (column: C18). The desired fractions were collected andlyophilized to afford the titled compound. ¹HNMR (300 MHz, (CD₃)₂SO) δ:10.65 (1H, s), 8.65 (1H, d, J=5.0 Hz), 7.35 (1H, s), 7.18 (1H, d, J=7.3Hz), 7.02 (1H, s), 6.65 (2H, d, J=7.3 Hz), 4.98 (1H, q, J=6.5 Hz), 3.78(3H, s), 3.70-3.40 (2H, m), 2.90-2.80 (2H, t, J=6.7 Hz), 2.70-2.60 (2H,t, J=6.7 Hz), 2.45-2.20 (7H, m), 1.90-1.75 (2H, m), 1.40-1.10 (6H, m),0.90 (3H, t, J=7.0 Hz). MS (ES) C₂₇H₃₆N₄O₅ requires: 496, found: 497(M+H)⁺.

Example 3145-Acetyl-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-iumtrifluoroacetate (OO1)

To a stirred solution of Example 304, EE6 in DMF under Ar was addedtributyl (1-ethoxyvinyl)stannane (2 eq.) and Pd(PPh₃)₄ (10 mol %). Thetemperature was raised to 110° C. and heating was continued for 48 hr.The solvent was removed under reduced pressure and the residue waspurified by flash chromatography on silica using 20% EtOAc/petroleumether as eluent to give a mixture of the 5-acetyl-(MS (ES) C₃₇H₅₆N₄O₇Sirequires: 696, found: 697 (M+H)⁺) and the 5-(1-ethoxyvinyl)-imidazole(MS (ES) C₃₉H₆₀N₄O₇Si requires: 725, found: 726 (M+H)⁺).

The purified mixture was dissolved in THF and a solution of 1 M TBAF inTHF (2.5 eq.) was added and the mixture was heated at 65° C. overnight.The reaction was quenched by addition of H₂O and the product extractedin DCM. The collected organic phases were washed with brine, dried(Na₂SO₄) and concentrated under reduced pressure to obtain a similarmixture of acetyl- and enol ether: tert-Butyl3-(2-{[(1S)-1-(5-acetyl-1H-imidazol-2-yl)-7-oxononyl]amino}-2-oxoethyl)-5-methoxy-2-methyl-1H-indole-1-carboxylate,MS (ES) C₃₁H₄₂N₄O₇ requires: 566, found: 567 (M+H)⁺; tert-butyl3-[2-({(1S)-1-[5-(1-ethoxyvinyl)-1H-imidazol-2-yl]-7-oxononyl}amino)-2-oxoethyl]-5-methoxy-2-methyl-1H-indole-1-carboxylate,MS (ES) C₃₃H₄₆N₄O₆ requires: 594, found: 595 (M+H)⁺.

This material was then dissolved in the minimum amount of DCM/TFA (1:1)mixture and stirred 1 hr. The reaction was quenched by addition of waterand the solvent removed under reduced pressure. The product was purifiedby preparative RP-HPLC, using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) aseluents (column: C18) and lyophilized to afford the titled compound.¹H-NMR (300 MHz, CDCl₃) δ: 8.00 (1H, s), 7.43 (1H, s), 7.08 (1H, d,J=7.3 Hz), 6.80-6.65 (2H, m), 6.35 (1H, br. s), 4.88 (1H, q, J=5.5 Hz),3.75 (3H, s), 3.63 (2H, s), 2.40-2.10 (10H, m), 1.90-1.10 (8H, m), 0.95(3H, t, J=7.0 Hz). MS (ES) C₂₆H₃₄N₄O₄ requires: 466, found: 467 (M+H)⁺.

Example 3155-Cyclohexyl-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-iumtrifluoroacetate (PP4) Step 1: tert-Butyl[(1S)-1-(4-cyclohex-1-en-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-7-oxononyl]carbamate(PP1)

The Suzuki coupling was carried out according to Example 304, step 7using cyclohex-1-en-1-ylboronic acid and tert-butyl[(is)-1-(4-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-7-oxononyl]carbamateto yield the desired compound. MS (ES) C₂₉H₅₁N₃O₄Si requires: 533,found: 534 (M+H)⁺.

Step 2: tert-Butyl[(1S)-1-(5-cyclohexyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-7-oxononyl]carbamate(PP2)

The cyclohexenylimidazole (PP1) was dissolved in EtOAc and stirred inthe presence of 10% Pd/C under an H₂ atmosphere for 1 hr. The H₂atmosphere removed and N₂ introduced. The reaction mixture was filteredand the catalyst washed with EtOAc and the filtrates concentrated underreduced pressure. The crude was purified by preparative RP-HPLC, usingH₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18). Thedesired fractions were collected and lyophilized to afford the desiredcompound. MS (ES) C₂₉H₄₉N₃O₄Si requires: 535, found: 536 (M+H)⁺

Step 3: (9S)-9-Amino-9-(5-cyclohexyl-1H-imidazol-2-yl)nonan-3-one (PP3)

The carbamate (PP2) was dissolved in the minimum amount of DCM/TFA (1:1)and stirred at RT for 1 hr. The reaction was quenched by addition ofwater and the solvent removed under reduced pressure. The product waspartitioned between DCM and sat. aq. NaHCO₃ solution. The organic phasewas separated, washed with brine, dried (Na₂SO₄) and concentrated underreduced pressure to obtain the desired amine. MS (ES). C₁₈H₃₁N₃Orequires: 305, found: 306 (M+H)⁺.

Step 4:5-Cyclohexyl-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-iumtrifluoroacetate (PP4)

The amine (PP3) was taken up in DMF and a solution of(5-methoxy-2-methyl-1H-indol-3-yl)acetic acid (1.3 eq.), HOBt (1.3 eq.)and EDC.HCl (1.3 eq.) in DMF (previously premixed for 5 min) was added,followed by DIPEA (1.3 eq.). The mixture was left stirring at RT for 3hr and was then purified by preparative RP-HPLC, using H₂O (+0.1% TFA)and MeCN (+0.1% TFA) as eluents (column: C18). The desired fractionswere collected and lyophilized to afford titled compound. ¹H NMR (300MHz, (CD₃)₂SO) δ: 10.65 (1H, s), 8.68 (1H, d, J=3.5 Hz), 7.35 (1H, s),7.18 (1H, d, J=7.3 Hz), 7.00 (1H, s), 6.68 (1H, d, J=7.3 Hz), 4.98 (1H,q, J=5.0 Hz), 3.80 (3H, s), 3.50-3.10 (2H, m), 2.75-2.50 (1H, m),2.50-2.30 (7H, m), 2.05-1.70 (6H, m), 1.50-1.10 (12H, m), 0.97 (3H, t,J=7.0 Hz). MS (ES) C₃₀H₄₂N₄O₃ requires: 506, found: 507 (M+H)⁺.

Example 3162-((1S)-1-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoundecyl)-5-phenyl-1H-imidazol-1-iumtrifluoroacetate (QQ4) Step 1: tert-Butyl(7S)-7-[(tert-butoxycarbonyl)amino]-7-(4-phenyl-1H-imidazol-2-yl)heptanoate(QQ1)

A solution Example 107, 13 and Cs₂CO₃ (0.6 eq) in EtOH was stirred for30 min at RT and then concentrated under reduced pressure.2-Bromo-1-phenylethanone (1.2 eq.) was added to the resulting salt inDMF and the mixture was stirred for 1.5 h at RT under N₂. The DMF wascoevaporated with toluene. EtOAc was added, the mixture was filtered andthe residue was washed with EtOAc. The combined filtrates wereconcentrated under reduced pressure. A solution of the resulting oil andNH₄OAc (20 eq.) in toluene was heated at reflux for 2 hr whilst excessNH₄OAc and H₂O were removed using a Dean-Stark trap. The mixture wascooled to RT, diluted with EtOAc and washed with water (×2), sat. aq.NaHCO₃ solution, water (×2) and brine. The solution was dried (Na₂SO₄),concentrated under reduced pressure and the resulting brown oil waspurified by chromatography on silica gel eluting with EtOAc/petroleumether (9:1 to 3:2) to obtain the title compound as a pale brown foam. ¹HNMR (400 MHz, DMSO-d6) δ: 11.75 (1H, s), 7.73 (2H, d, J=7.5 Hz), 7.76(1H, s), 7.31, (2H, t, J=7.5 Hz), 7.18-7.11 (1H, m), 7.05 (1H, d, J=8.1Hz), 4.63-4.51 (1H, m), 2.15 (2H, t, J=7.2 Hz), 1.87-1.75 (1H, m),1.75-1.64 (1H, m), 1.52-1.43 (2H, m), 1.38 (18H, s), 1.33-1.18 (4H, m).MS (ES) C₂₅H₃₇N₃O₄ requires: 443, found: 444 (M+H)⁺.

Step 2: 2-[(1S)-1-Ammonio-6-carboxyhexyl]-5-phenyl-1H-imidazol-3-iumbis(trifluoroacetate) (QQ2)

The imidazole (QQ1) (1 eq.) was dissolved in TFA/DCM (1:1) at 0° C., thecooling bath was removed and the mixture was stirred for 2 h at RT. Thesolvents were then removed under reduced pressure and the crude was usedas such without any further purification. MS (ES) C₁₆H₂₁N₃O₂ requires:287, found: 288 (M+H)⁺.

Step 3:(7S)—N-methoxy-7-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-N-methyl-7-(5-phenyl-1H-imidazol-2-yl)heptanamide(QQ3)

A solution of EDC.HCl (1.2 eq.), HOBt (1.2 eq.) and(5-methoxy-2-methyl-1H-indol-3-yl)acetic acid (1.2 eq.) in DMF wasstirred for 1 hr at RT and was then added to a solution of the amine(QQ2) (1 eq.) and DIPEA (2 eq.) in DMF. The mixture was stirredovernight then more HATU (2 eq.) was added followed after 1 h byCH₃ON(CH₃)H.HCl (2 eq.). After stirring for a further 12 hours the crudewas purified by preparative RP-HPLC, using H₂O (0.1% TFA) and MeCN(+0.1% TFA) as eluents (column: C18). The desired fractions werelyophilized to afford the titled compound as a white solid. The compoundwas then extracted from sat. aq. NaHCO₃ solution to obtain the freebase. ¹H NMR (400 MHz, DMSO-d6) δ: 10.62 (1H, s), 8.62 (1H, d, J=6.3Hz), 8.03 (1H, s), 7.77 (2H, d, J=7.6 Hz), 7.52 (2H, t, J=7.6 Hz),7.48-7.39 (1H, m), 7.10 (1H, d, J=8.6 Hz), 6.96 (1H, s), 6.64-6.56 (2H,m), 5.06-4.96 (1H, m), 3.69 (3H, s), 3.62 (3H, s), 3.60-3.45 (2H, m),3.06 (3H, s), 2.35-2.26 (2H, m), 2.36-2.26 (5H, m), 1.50-1.18 (6H, m).MS (ES) C₃₀H₃₇N₅O₄ requires: 531, found: 532 (M+H)⁺.

Step 4:2-((1S)-1-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoundecyl)-5-phenyl-1H-imidazol-1-iumtrifluoroacetate (QQ4)

To a solution of QQ3 in THF (2 mL) at −78° C. was added n-BuLi (5 eq.).After 1 hr, the reaction mixture was quenched carefully with H₂O. Afterwarming to RT the aqueous phase was extracted with EtOAc, the combinedorganic phases were dried (MgSO₄) and the solvent was removed underreduced pressure. The desired material was isolated by preparativeRP-HPLC, using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18column) to yield after lyophilisation the imidazole as a white solid.

¹H NMR (300 MHz, CDCl₃) δ: 10.23 (1H, d, J=6.9 Hz), 8.25 (1H, s),7.52-7.32 (6H, m), 7.13 (1H, d, J=8.5 Hz), 6.87 (1H, m), 6.73 (1H, d,J=8.5 Hz), 5.88 (1H, m), 5.44 (1H, m), 3.73 (2H, s), 3.62 (3H, s), 2.35(6H, m), 2.27 (3H, s), 1.98 (2H, m), 1.60-0.94 (8H, m), 0.89 (3H, t,J=7.2 Hz). MS (ES) C₃₂H₄₀N₄O₃ requires: 529, found: 530 (M+H)⁺.

Example 3172-((1S)-7-Cyclopropyl-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-phenyl-1H-imidazol-1-iumtrifluoroacetate (RR1)

This material was obtained as described for Example 316 using QQ3 andcyclopropylmagnesium bromide. ¹H NMR (300 MHz, CDCl₃) δ: 10.32 (1H, d,J=8.0 Hz), 8.31 (1H, s), 7.52-7.31 (5H, m), 7.12 (1H, d, J=8.6 Hz), 6.89(1H, d, J=1.5 Hz), 6.73 (1H, dd, J=8.6 Hz, J=1.5 Hz), 5.88 (1H, m), 5.43(1H, m), 3.73 (2H, s), 3.62 (3H, s), 2.48 (2H, m), 2.27 (3H, s),2.05-1.86 (4H, m), 1.50 (2H, m), 1.24 (3H, m), 0.98 (3H, m), 0.86 (2H,m). MS (ES) C₃₁H₃₆N₄O₃ requires: 513, found: 514 (M+H)⁺.

Example 3182-((1S)-1-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-9-methyl-7-oxodecyl)-5-phenyl-1H-imidazol-1-iumtrifluoroacetate (SS1)

This material was obtained as described for Example 316 using QQ3 andisobutylmagnesium bromide. ¹H NMR (300 MHz, CDCl₃) δ: 10.60 (1H, d,J=8.0 Hz), 8.19 (1H, s), 7.53-7.32 (5H, m), 7.14 (1H, d, J=8.6 Hz), 6.91(1H, d, J=2.0 Hz), 6.75 (1H, dd, J=8.6 Hz, J=2.0 Hz), 5.75 (1H, br s),5.46 (1H, m), 3.75 (2H, s), 3.62 (3H, s), 2.37-1.69 (10H, m), 1.46 (2H,m), 1.33-1.00 (5H, m), 0.90 (3H, d, J=6.6 Hz), 0.89 (3H, d, J=6.6 Hz).MS (ES) C₃₂H₄₀N₄O₃ requires: 529, found: 530 (M+H)⁺.

Example 3192-((1S)-8-hydroxy-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-iumtrifluoroacetate (TT1)

To a solution of chloroiodomethane (5.3 eq.) in THF at −78° C. wasslowly added a solution of MeLi in Et₂O (5.3 eq.), after 5 min thesolution was transferred via cannula to a solution of Example 316 QQ3 (1eq.) in THF at −78° C. The reaction was stirred at −78° C. for 2 hr andwas then quenched by carefully addition of water. After warning to RTthe aqueous phase was extracted with EtOAc. The combined organic phasewas dried (MgSO₄) and solvent was removed under reduced pressure.

The crude was solved in DMF (3 mL) and treated with potassium acetate (1eq.) for 2 hr at 60° C. The reaction mixture was diluted with EtOAc andwashed with brine (2×). The organic phase was dried (MgSO₄) and thesolvents were removed under reduced pressure. The crude acetate wasdissolved in MeOH (3 mL) and treated with sodium carbonate (1 eq.) for30 min at RT. Water was added and the aqueous phase was extracted withEtOAc. The combined organic phase was dried (MgSO₄) and concentratedunder reduced pressure. The desired material was isolated by preparativeRP-HPLC, using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18column) to yield the imidazole as a colourless oil. ¹H NMR (300 MHz,CDCl₃) δ: 10.60 (1H, s), 8.56 (1H, br s), 7.99 (1H, s), 7.75 (2H, d,J=7.5 Hz), 7.53-7.37 (3H, m), 7.09 (1H, d, J=8.8 Hz), 6.95 (1H, d, J=2.0Hz), 6.59 (1H, dd, J=2.0 Hz, J=8.8 Hz), 4.99 (1H, m), 4.00 (2H, s), 3.67(3H, s), 3.51 (2H, m), 2.29 (5H, m), 1.88 (2H, m), 1.45-1.12 (8H, m). MS(ES) C₂₉H₃₄N₄O₄ requires: 502, found: 503 (M+H)⁺.

Example 3202-((1S)-7-(2-Furyl)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate (UU1)

To a solution of furan (10 eq.) in THF at −78° C. was slowly added asolution of n-BuLi in hexane (10 eq.). The solution was then warmed to0° C. and stirred at 0° C. for 1.5 h. After cooling to −78° C. it wastransferred via cannula to a solution of(7S)—N-methoxy-7-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-N-methyl-7-[5-(2-naphthyl)-1H-imidazol-2-yl]heptanamide(1 eq.) (Prepared in a similar manner to Example 316, QQ3) in THF at−78° C. The reaction mixture was allowed to warm up to RT overnight andthen was quenched carefully with water. The aqueous phase was extractedwith EtOAc. The combined organic phase was dried (MgSO₄) and solvent wasremoved under reduced pressure. The desired material was isolated bypreparative RP-HPLC, using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) aseluents (C18 column) to afford the imidazole O1 as a white solid. ¹H NMR(300 MHz, DMSO) δ: 10.61 (1H, s), 8.64 (1H, d, J=5.8 Hz), 8.33 (1H, s),8.14 (1H, s), 8.04 (1H, d, J=8.8 Hz), 7.99-7.86 (4H, m), 7.58 (2H, m),7.38 (1H, dd, J=0.7 Hz, J=3.6 Hz), 7.08 (1H, d, J=8.8 Hz), 6.97 (1H, d,J=2.4 Hz), 6.67 (1H, dd, J=1.6 Hz, J=3.6 Hz), 6.57 (1H, dd, J=2.4 Hz,J=8.6 Hz), 5.04 (1H, m), 3.65 (3H, s), 3.53 (2H, dt, J=14.7 Hz, J=14Hz), 2.74 (2H, t, J=7.3 Hz), 2.30 (3H, s), 1.94 (2H, m), 1.58-1.17 (6H,m). MS (ES) C₃₆H₃₆N₄O₄ requires: 589, found: 590 (M+H)⁺.

Example 3212-[(1S)-1-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-8-(methylsulfinyl)-7-oxooctyl]-5-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate (VV1)

To a solution of DMSO (15 eq.) in THF at −78° C. was slowly added n-BuLisolution in hexane (15 eq.), after 30 min the solution was transferredvia cannula to a solution of(7S)—N-methoxy-7-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-N-methyl-7-[5-(2-naphthyl)-1H-imidazol-2-yl]heptanamide(1 eq.) (Prepared in a similar manner to Example 316, QQ3) in THF at−78° C. The reaction mixture was allowed to warm up to RT overnight andwas then quenched by carefully addition of water. The aqueous phase wasextracted with EtOAc, dried (MgSO₄) and then solvent was removed underreduced pressure. The desired material was isolated by preparativeRP-HPLC, using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18column) and lyophilized to afford the imidazole as a colourless oil. ¹HNMR (300 MHz, CDCl₃) δ: 10.10 (1H, br s), 8.25 (1H, s), 8.11 (1H, s),7.88-7.73 (3H, m), 7.58-7.46 (2H, m), 7.43-7.34 (1H, m), 7.15 (1H, d,J=8.6 Hz), 6.91 (1H, d, J=1.7 Hz), 6.74 (1H, dd, J=1.7 Hz, J=8.6 Hz),6.11 (1H, d, J=15 Hz), 5.48 (1H, m), 3.77 (4H, s), 3.62 (3H, s), 2.69(3H, s), 2.47 (2H, m), 2.30 (3H, s), 2.15-1.92 (2H, m), 1.53 (2H, m),1.37-1.04 (4H, m). MS (ES) C₃₄H₃₉N₄O₄S requires: 599, found: 600 (M+H)⁺.

Example 3222-[(1S)-1-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-8-(methylsulfonyl)-7-oxooctyl]-5-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate (WW1)

This material was obtained as described for Example 321 usingdimethylsulfone. ¹H NMR (300 MHz, DMSO) δ: 10.83 (1H, s), 8.84 (1H, d,J=6.4 Hz), 8.54 (1H, s), 8.37 (1H, s), 8.26 (1H, d, J=8.6 Hz), 8.21-8.06(4H, m), 7.80 (2H, m), 7.31 (1H, d, J=8.6 Hz), 7.18 (1H, d, J=2.0 Hz),6.80 (1H, dd, J=2.0 Hz, J=8.6 Hz), 5.26 (1H, m), 4.64 (2H, s), 3.88 (3H,s), 3.75 (2H, m), 3.26 (3H, s), 2.77 (2H, t, J=7.0 Hz), 2.52 (3H, s),2.15 (2H, m), 1.70-1.36 (6H, m). MS (ES) C₃₄H₃₈N₄O₅S requires: 615,found: 616 (M+H)⁺.

Example 3232-((1S)-8-(Aminosulfonyl)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate (XX1)

To a solution of tert-butyl (methylsulfonyl)carbamate (15 eq.) in THF at−78° C. was slowly added a solution of n-BuLi in hexane (30 eq.), after30 min the solution was transferred via cannula to a solution of(7S)—N-methoxy-7-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-N-methyl-7-[5-(2-naphthyl)-1H-imidazol-2-yl]heptanamide(1 eq.) (Prepared in a similar manner to Example 316, QQ3) in THF at−78° C. The reaction mixture was allowed to warm up to RT overnight andwas then quenched carefully with water. The aqueous phase was extractedwith EtOAc and was dried (MgSO₄) and solvent was removed under reducedpressure.

The crude was resolved in DCM/TFA (3:1) and stirred for 1 h. Thesolvents were removed under reduced pressure and the desired materialwas isolated by preparative RP-HPLC, using H₂O (+0.1% TFA) and MeCN(+0.1% TFA) as eluents (C18 column) to yield the imidazole as a whitesolid. ¹H NMR (300 MHz, DMSO) δ: 10.61 (1H, s), 8.60 (1H, m), 8.32 (1H,s), 8.13 (1H, s), 8.05 (1H, d, J=8.6 Hz), 7.99-7.84 (4H, m), 7.58 (2H,m), 7.09 (3H, m), 6.96 (1H, d, J=2.4 Hz), 6.58 (1H, dd, J=2.4 Hz, J=8.6Hz), 5.03 (1H, m), 4.15 (2H, s), 3.66 (3H, s), 3.59 (2H, m), 2.60 (2H,t, J=7.0 Hz), 2.30 (3H, s), 1.93 (2H, m), 1.48-1.15 (8H, m). MS (ES)C₃₃H₃₇N₅O₅S requires: 616, found: 617 (M+H)⁺.

Example 3241-Methyl-4-({[(1S)-7-oxo-1-(4-phenyl-1H-imidazol-3-ium-2-yl)-7-pyridin-2-ylheptyl]amino}carbonyl)piperidiniumbis(trifluoroacetate) (YY8) Step 1: tert-Butyl(7S)-7-[(tert-butoxycarbonyl)amino]-7-(5-phenyl-1H-imidazol-2-yl)heptanoate(YY1)

A solution (0.5 M) of[(2S)-8-tert-butoxy-2-[(tert-butoxycarbonyl)amino]-8-oxooctanoic acid inEtOH was treated with Cs₂CO₃ (0.5 eq.). The reaction mixture was stirredat RT for 50 min then the solvent was evaporated under reduced pressureand then the resulting salt was dissolved in DMF and was treated with2-bromo-1-phenylethanone (1.0 eq.). The reaction mixture was stirred for1 h at RT then the DMF was coevaporated with toluene. The residue wassuspended in EtOAc and filtrate. The filtrate was concentrated underreduced pressure to give an oil that was dissolved in toluene. Theresulting solution (0.14 M) was treated with NH₄OAc (20 eq.) and heatedat reflux with a Dean Stark trap for 2 h. The reaction mixture wascooled down to RT and diluted with EtOAc and a sat. aq. NaHCO₃ solution.The organic layers were washed with brine, dried and concentrated underreduced pressure to give an oil which was purified by chromatography onsilica gel eluting with 20% EtOAc/petroleum ether/EtOAc to afford thetitle compound as a solid. ¹H NMR (400 MHz, DMSO-d₆, 300 K) δ 11.77 (1H,s), 7.75 (2H, d, J=7.3 Hz), 7.48 (1H, s), 7.33 (2H, t, J=7.6 Hz), 7.17(1H, t, J=7.3 Hz), 7.12-7.02 (1H, m), 4.70-4.50 (1H, m), 2.17 (2H, t,J=7.3 Hz), 1.93-1.63 (2H, m), 1.57-1.15 (24H, m); MS (ES) C₂₅H₃₇N₃O₄requires: 443, found: 444 (M+H)⁺.

Step 2:(7S)-7-{1-[(Benzyloxy)methyl]-5-phenyl-1H-imidazol-2-yl}-7-[(tert-butoxycarbonyl)amino]heptanoicacid (YY2)

A solution the imidazole (YY1) in MeCN was treated with[(chloromethoxy)methyl]benzene (1.2 eq.) and stirred at reflux for 3 h.The reaction mixture was cooled to RT, the solvent was evaporated underreduced pressure and the residue was diluted with H₂O and extracted withEtOAc. The collected organic layers were washed with brine, dried andconcentrated under reduced pressure to give an oil residue containing amixture of the tert-butyl(7S)-7-{1-[(benzyloxy)methyl]-5-phenyl-1H-imidazol-2-yl}-7-[(tert-butoxycarbonyl)amino]heptanoateand tert-butyl(7S)-7-amino-7-{1-[(benzyloxy)methyl]-5-phenyl-1H-imidazol-2-yl}heptanoatethat was used without further purification. MS (ES) C₃₃H₄₅N₃O₅ requires:563, found: 564 (M+H)⁺.

The above mixture in DCM/TFA (4:1) was stirred at 0° C. then the coolingbath was removed and the reaction mixture was stirred at RT for 1 h. Thesolvents were removed under reduced pressure and the residue wascoevaporated with toluene to give desired compounds that was usedwithout any further purification. MS (ES) C₂₄H₂₉N₃O₃ requires: 407,found: 408 (M+H)⁺.

A solution of the above intermediate in H₂O/MeCN was cooled to 0° C. andtreated with NaHCO₃ (3.0 eq.) and Boc₂O (1.5 eq.). The reaction mixturewas stirred at RT for 2 h. The CH₃CN was removed under reduced pressureand the aqueous phase was extracted with EtOAc. The pH was adjusted topH 4-5 with 1N HCl and was extracted again. The collected organic phaseswere washed with brine, dried and concentrated under reduced pressure toyield an amber oil which was purified by chromatography on silica geleluting with 50-60% EtOAc/petroleum ether to afford the title compound(92%) as a pale amber oil. ¹H NMR (400 MHz, DMSO-d₆, 300 K) δ 8.11 (1H,s), 7.81 (2H, d, J=7.5 Hz), 7.50 (2H, t, J=7.7 Hz), 7.41-7.28 (7H, m),5.81 (1H, d, J=10.2 Hz), 5.64 (1H, d, J=10.2 Hz), 4.96-4.86 (1H, m),4.69-4.59 (2H, m), 2.17 (2H, t, J=7.3 Hz), 1.97-1.85 (2H, m), 1.55-1.43(15H, m); MS (ES) C₂₉H₃₇N₃O₅ requires: 507, found: 508 (M+H)⁺.

Step 3: tert-Butyl((1S)-1-{1-[(benzyloxy)methyl]-5-phenyl-1H-imidazol-2-yl}-7-hydroxyheptyl)carbamate(YY3)

A solution the above acid (YY2) in THF was treated with4-methylmorpholine (2.0 eq.) and cooled to 0° C. The resulting solutionwas treated dropwise with isobutyl chloridocarbonate (2.0 eq.) and wasthen stirred for 15 min at 0° C., during which period a whiteprecipitate formed. The precipitate was filtered off and the filtratewas treated dropwise at 0° C. with NaBH₄ (2.5 eq.) in H₂O (0.6 M). Thereaction mixture was stirred for 15 min at the same temperature then itwas warmed up to RT and the THF was removed under reduced pressure. Theresidue was diluted with H₂O and extracted with EtOAc. The collectedorganic layers were washed with brine, dried and concentrated underreduced pressure to give a yellow oil. The purification bychromatography on silica gel eluting with 30% EtOAc/petroleum etherafforded the title compound as a pale yellow solid. ¹H NMR (400 MHz,DMSO-d₆, 300 K) δ 8.26 (1H, s), 7.83-7.76 (3H, m), 7.57-7.50 (2H, m),7.49-7.43 (1H, m), 7.38-7.26 (5H, m), 5.86 (1H, d, J=10.7 Hz), 5.74 (1H,d, J=10.7 Hz), 5.04-4.94 (1H, m), 4.68 (2H, s), 3.36 (2H, t, J=6.6 Hz),2.05-1.81 (2H, m), 1.47-1.17 (15H, m).

Step 4: tert-Butyl((1S)-1-{1-[(benzyloxy)methyl]-5-phenyl-1H-imidazol-2-yl}-7-oxoheptyl)carbamate(YY4)

A solution the alcohol (YY3) in DCM was treated with pyridine (4.2 eq.)and the Dess-Martin Periodinane (2.0 eq.). The reaction mixture wasstirred for 3 hr then the reaction mixture was diluted with sat. aq.Na₂CO₃ solution and extracted with DCM. The collected organic phaseswere washed with brine, dried and concentrated under reduced pressure toafford the title compound as a colorless oil. ¹H NMR (400 MHz, CDCl₃,300 K) δ 9.71 (1H, s), 7.80 (2H, d, J=7.5 Hz), 7.43-7.23 (8H, m), 7.20(1H, s), 5.68 (1H, d, J=10.6 Hz), 5.38-5.24 (1H, bs), 5.28 (1H, d,J=10.6 Hz), 5.00-4.89 (1H, m), 4.54 (2H, s), 2.36 (2H, t, J=6.6 Hz),2.08-1.89 (2H, m), 1.63-1.53 (2H, m), 1.43 (9H, s), 1.41-1.30 (4H, m);MS (ES) C₂₉H₃₇N₃O₄ requires: 491, found: 492 (M+H)⁺.

Step 5: tert-Butyl((1S)-1-{1-[(benzyloxy)methyl]-5-phenyl-1H-imidazol-2-yl}-7-hydroxy-7-pyridin-2-ylheptyl)carbamate(YY5)

A solution of 2-bromopyridine (2.05 eq.) in THF was cooled to −78° C.and treated with a 1.6 M solution of n-BuLi in hexanes (2.1 eq.) Theresulting orange solution was stirred at −78° C. for 30 min then it wastreated with a solution the aldehyde (YY4) in THF. The resulting paleyellow solution was left to reach RT overnight and was then cooled to 0°C. and quenched with sat. aq. NH₄Cl solution and extracted with EtOAc.The collected organic phases were washed with brine, dried andevaporated under reduced pressure. The resulting yellow oil was purifiedby chromatography on silica gel eluting with 30-50% EtOAc/petroleumether to afford the title compound as a pale yellow oil. ¹H NMR (400MHz, DMSO-d₆, 300 K) δ 8.46 (1H, d, J=4.6 Hz), 7.82-7.69 (4H, m), 7.45(1H, d, J=7.9 Hz), 7.41-7.26 (8H, m), 7.25-7.16 (2H, m), 5.66 (1H, d,J=10.6 Hz), 5.42 (1H, d, J=10.6 Hz), 5.25 (1H, d, J=5.0 Hz), 4.80-4.68(1H, m), 4.60-4.46 (2H, m), 3.36-2.28 (2H, m), 1.92-1.77 (2H, m),1.76-1.64 (1H, m), 1.63-1.49 (1H, m), 1.35 (9H, s), 1.36-1.22 (4H, m);MS (ES) C₃₄H₄₂N₄O₄ requires: 570, found: 571 (M+H)⁺.

Step 6: tert-Butyl((1S)-1-{1-[(benzyloxy)methyl]-5-phenyl-1H-imidazol-2-yl}-7-oxo-7-pyridin-2-ylheptyl)carbamate(YY6)

A solution the alcohol (YY5) in DCM was treated with pyridine (4.2 eq.)and the Dess-Martin Periodinane (2.0 eq.). The reaction mixture wasstirred for 3 h then the crude material was diluted with sat. aq. Na₂CO₃solution and extracted with DCM. The collected organic phases werewashed with brine, dried and concentrated under reduced pressure toafford a brown oil which was purified by chromatography on silica geleluting with 20-30% EtOAc/petroleum ether to yield the desired materialas a pale yellow oil.

¹H NMR (400 MHz, CDCl₃, 300 K) δ 8.67 (1H, d, J=4.6 Hz), 8.02 (1H, d,J=7.9 Hz), 7.99-7.89 (2H, m), 7.83 (1H, td, J=1.3 Hz, J=7.7 Hz),7.53-7.30 (10H, m), 7.17 (1H, s), 5.96-5.84 (1H, m), 5.49-5.36 (1H, m),5.13-5.01 (1H, m), 4.74-4.59 (2H, m), 3.19 (2H, t, J=7.2 Hz), 2.54-2.36(1H, m), 2.23-2.09 (1H, m), 1.79-1.63 (2H, m), 1.50-1.22 (4H, m), 1.42(9H, s); MS (ES) C₃₄H₄₀N₄O₄ requires: 568, found: 569 (M+H)⁺.

Step 7:N-((1S)-1-{1-[(Benzyloxy)methyl]-5-phenyl-1H-imidazol-2-yl}-7-oxo-7-pyridin-2-ylheptyl)-1-methylpiperidine-4-carboxamide(YY7)

The ketone (YY6) was treated at 0° C. with a mixture TFA/DCM (1:4), thenthe cooling bath was removed and the reaction mixture was stirred at RTfor 1 h. The solvents were removed under reduced pressure and theresidue was coevaporated with toluene to give a crude material that wasused without any further purification. MS (ES) C₂₉H₃₂N₄O₂ requires: 468,found: 469 (M+H)⁺.

A solution of 1-methylpiperidine-4-carboxylic acid in DMF was treated at0° C. with EDC hydrochloride (1.2 eq.), HOBt (1.2 eq.) and Et₃N (4.2eq.) and the mixture was stirred at 0° C. for 30 min, then a solution ofthe above intermediate in DMF was added and the reaction mixture wasstirred overnight at RT. The reaction mixture was diluted with 2N NaOHand extracted with EtOAc. The collected organic phases were washed withbrine, dried and evaporated under reduced pressure to give the titlecompound as a pale yellow solid which was used in the next step withoutany purification. ¹H NMR (400 MHz, DMSO-d₆, 300 K) δ 8.71 (1H, d, J=4.4Hz), 8.28 (1H, d, J=8.3 Hz), 8.01 (1H, dt, J=1.5 Hz, J=7.7 Hz), 7.95(1H, d, J=7.7 Hz), 7.81-7.72 (3H, m), 7.69-7.62 (1H, m), 7.41-7.24 (7H,m), 7.21 (1H, t, J=7.3 Hz), 5.65 (1H, d, J=10.7 Hz), 5.39 (1H, d, J=10.7Hz), 5.12-5.01 (1H, m), 4.56 (1H, d, J=11.6 Hz), 4.51 (1H, d, J=11.6Hz), 3.12 (2H, t, J=7.3 Hz), 3.04-2.95 (2H, m), 2.76-2.63 (2H, m),2.22-2.16 (1H, m), 2.14-2.04 (4H, m), 2.00-1.83 (2H, m), 1.82-1.67 (2H,m), 1.67-1.42 (4H, m), 1.41-1.19 (4H, m); MS (ES) C₃₆H₄₃N₅O₃ requires:593, found: 594 (M+H)⁺.

Step 8:1-Methyl-4-({[(1S)-7-oxo-1-(4-phenyl-1H-imidazol-3-ium-2-yl)-7-pyridin-2-ylheptyl]amino}carbonyl)piperidiniumbis(trifluoroacetate) (YY8)

A solution of the amide (YY7) in toluene at 0° C. was treated with BBr₃(3.0 eq.). The reaction mixture was stirred at RT overnight then it wasdiluted with water and concentrated under reduced pressure. The residuewas purified by RP-HPLC (Waters X-TERRA MS C18, 5 micron, 19×150 mm)using H₂O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents to afford thetitle compound as an oil. ¹H NMR (400 MHz, DMSO-d₆, 300 K) δ 8.80-8.62(2H, m), 8.08-7.91 (3H, m), 7.79 (2H, d, J=7.5 Hz), 7.72-7.64 (1H, m),7.59-7.35 (3H, m), 5.07-4.95 (1H, m), 3.53-3.38 (2H, m), 3.23-3.12 (2H,m), 3.03-2.87 (2H, m), 2.79 (3H, s), 2.53-2.42 (1H, m), 2.09-1.83 (4H,m), 1.81-1.58 (4H, m), 1.48-1.21 (4H, m); MS (ES) C₂₈H₃₅N₂O₂ requires:473, found: 474 (M+H)⁺.

Example 3252-((1S)-7-Amino-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-3-iumtrifluoroacetate (ZZ7) Step 1: 8-tert-Butyl 1-methyl(2S)-2-{[(benzyloxy)carbonyl]amino}octanedioate (ZZ1)

Example 107, 11 (1 eq.) was dissolved in THF and cooled at 0° C.; 1M HClwas added (4 eq.) and the mixture was stirred 20 min. 1M NaOH was added(4 eq), the aqueous phase was extracted with EtOAc and the collectedorganic phases were treated with brine, dried (Na₂SO₄) and the solventremoved under reduced pressure. The pale yellow oil obtained wasdissolved in DCM and Et₃N was added (1.5 eq.). To this mixture asolution of N-(benzyloxycarbonyloxy)succinimide (1.3 eq) in DCM wasadded and stirring for a 1 hr at RT the solvents were removed underreduced pressure. The yellow oil was purified by chromatography onsilica gel eluting with 5-50% EtOAc/petroleum ether to obtain the titlecompound as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.42-7.28 (5H,m), 5.24 (1H, d, J=7.7 Hz), 5.11 (2H, s), 4.41-4.32 (1H, m), 3.74 (3H,s), 2.19 (2H, t, J=7.5 Hz), 1.89-1.77 (1H, m), 1.70-1.50 (3H, m), 1.44(9H, s), 1.38-1.24 (4H, m). MS (ES) C₂₁H₃₁NO₆ requires: 393, found: 394(M+H)⁺.

Step 2: (2S)-2-{[(Benzyloxy)carbonyl]amino}-8-tert-butoxy-8-oxooctanoicacid (ZZ2)

The above ester (ZZ1) (1 eq.) was dissolved in a THF/H₂O (4:1) andLiOH.H₂O (1.1 eq.) was added, the mixture was stirred for 1.5 hr. 1M HClwas added until pH 4-5 and the THF was removed under reduced pressure.The aqueous phase was extracted with EtOAc (3×); the collected organicphases were washed with brine and then dried (Na₂SO₄). The solvent wereremoved under reduced pressure to yield the title compound was as acolorless oil which solidified upon standing. MS (ES) C₂₀H₂₉NO₆requires: 379, found: 380 (M+H)⁺.

Step 3: tert-Butyl(7S)-7-{[(benzyloxy)carbonyl]amino}-7-[5-(2-naphthyl)-1H-imidazol-2-yl]heptanoate(ZZ3)

A mixture of the acid (ZZ2) (1 eq.) and Cs₂CO₃ (0.5 eq) in EtOH wasstirred for 30 min at RT and then concentrated under reduced pressure.2-2-Bromo-1-(2-naphthyl)ethanone (1 eq.) was added to the resulting saltin DMF and the mixture was stirred for 1.5 h at RT under N₂. The DMF wascoevaporated with toluene. EtOAc was added, the mixture was filtered andthe residue was washed with EtOAc. The combined filtrates wereconcentrated under reduced pressure. A solution of the resulting oil andNH₄OAc (20 eq.) in toluene was heated at reflux for 2 hr while excessNH₄OAc and H₂O were removed using a Dean-Stark trap. The mixture wascooled to RT, diluted with EtOAc and washed with water (×2), sat. aq.NaHCO₃ solution, water (×2) and brine. The solution was dried (Na₂SO₄),concentrated under reduced pressure and the resulting brown oil waspurified by chromatography on silica gel eluting with EtOAc/petrol etherto obtain the title compound as a pale brown foam. ¹H NMR (400 MHz,CDCl₃) δ: 7.95-7.70 (5H, m), 7.56-7.41 (3H, m), 7.39-7.30 (5H, m), 5.59(1H, bs), 5.19-5.10 (2H, m), 4.83-4.72 (1H, m), 2.22 (2H, t, J=7.4 Hz),2.09-1.97 (1H, m), 1.82-1.55 (5H, m), 1.45 (9H, s), 1.49-1.38 (2H, m).MS (ES) C₃₂H₃₇N₃O₄ requires: 528, found: 529 (M+H)⁺.

Step 4:(7S)-7-{[(Benzyloxy)carbonyl]amino}-7-[5-(2-naphthyl)-1H-imidazol-2-yl]heptanoicacid (ZZ4)

The imidazole (ZZ3) (1 eq.) was dissolved in TFA/DCM (1:1) at 0° C., thecooling bath was removed and the mixture was stirred for 60 min at RT.The solvents were removed under reduced pressure and the residue waspurified by chromatography on silica gel eluting with EtOAc/AcOH (99:1)to obtain the title compound as a pale brown foam. ¹H NMR (400 MHz,DMSO-d6) δ: 11.99 (1H, bs), 8.34 (1H, s), 8.10-7.98 (3H, m), 7.98-7.76(3H, m), 7.63-7.50 (2H, m), 7.43-7.28 (4H, m), 5.16-4.98 (2H, m),4.90-4.80 (1H, m), 2.19 (2H, t, J=7.2 Hz), 2.00-1.83 (2H, m), 1.56-1.44(2H, m), 1.42-1.24 (4H, m). MS (ES) C₂₈H₂₉N₃O₄ requires: 471, found: 472(M+H)⁺.

Step 5: Benzyl{(1S)-7-amino-1-[5-(2-naphthyl)-1H-imidazol-2-yl]-7-oxoheptyl}carbamate(ZZ5)

The acid (ZZ4) (1 eq.) was dissolved in DMF in an ace tube, HATU (2 eq.)and DIPEA (2 eq.) were added and the mixture was stirred 1 h at RT. Asolution of NH₃ in dioxane (0.5 N, 5 eq.) was added and after stirring 3h at RT solvents were removed under reduced pressure. The crude was usedas such in the following reaction. MS (ES) C₂₈H₃₀N₄O₃ requires: 470,found: 471 (M+H)⁺.

Step 6: (7S)-7-Amino-7-[5-(2-naphthyl)-1H-imidazol-2-yl]heptanamide(ZZ6)

A solution of the amide (ZZ5) (1 eq.) in MeOH was cooled at 0° C. underN₂, then Pd/C (10% wt) was added. After two vacuum-H₂ cycles the mixturewas stirred 2.5 hr under an H₂ atmosphere. The catalyst was filtered offand washed with MeOH then the solvent was removed under reducedpressure. The crude was used as such in the following reaction. MS (ES)C₂₀H₂₄N₄O requires: 336, found: 337 (M+H)⁺.

Step 7:2-((1S)-7-Amino-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-3-iumtrifluoroacetate (ZZ7)

A solution of EDC.HCl (1.2 eq.), HOBt (1.2 eq.) and(5-methoxy-2-methyl-1H-indol-3-yl)acetic acid (1.2 eq.) in DCM wasstirred for 1 hr at RT then it was added to a solution of the amine(ZZ6) in DMF. The mixture was stirred overnight at RT then the crude wasdirectly purified by preparative RP-HPLC, using H₂O (0.1% TFA) and MeCN(+0.1% TFA) as eluents (column: C18). The desired fractions werelyophilized to afford the titled compound as a white solid. ¹H NMR (400MHz, DMSO-d6) δ: 10.62 (1H, s), 8.61 (1H, d, J=6.3 Hz), 8.34 (1H, s),8.16 (1H, s), 8.07 (1H, d, J=8.8 Hz), 8.01-7.93 (2H, m), 7.90 (1H, ddJ=8.6, J₂=1.8 Hz), 7.66-7.55 (2H, m), 7.19 (1H, s), 7.10 (1H, d, J=8.6Hz), 6.97 (1H, d, J=2.3 Hz), 6.67 (1H, s), 6.62 (1H, dd J=8.6, J₂=2.3Hz), 5.10-5.00 (1H, m), 3.68 (3H, s), 3.64-3.48 (2H, m), 2.32 (3H, s),2.00 (2H, t, J=7.3 Hz), 2.05-1.87 (2H, m), 1.52-1.32 (3H, m), 1.32-1.20(3H, m). MS (ES) C₃₂H₃₅N₅O₃ requires: 537, found: 538 (M+H)⁺.

Example 3262-((1S)-6-Carboxy-1-{[(dimethylamino)sulfonyl]amino}hexyl)-5-(2-naphthyl)-1H-imidazol-3-iumtrifluoroacetate (AAA1)

A solution of Example 107, 15 (1 eq.), DIPEA (2 eq.) anddimethylsulfamoyl chloride (2 eq.) in DMF was stirred overnight at RT.The crude was purified by preparative RP-HPLC, using H₂O (0.1% TFA) andMeCN (+0.1% TFA) as eluents (column: C18) and the desired fractions werelyophilized to afford the titled compound as a white solid. ¹H NMR (400MHz, DMSO-d6) δ: 12.04 (1H, bs), 8.33 (1H, s), 8.12 (1H, bs), 8.09-8.00(2H, m), 7.99-7.87 (3H, m), 7.63-7.52 (2H, m), 4.62-4.51 (1H, m), 2.63(6H, s), 2.19 (2H, t, J=7.2 Hz), 2.02-1.84 (2H, m), 1.55-1.44 (2H, m),1.44-1.35 (1H, m), 1.35-1.16 (3H, m). MS (ES) C₂₂H₂₈N₄O₄S requires: 444,found: 445 (M+H)⁺.

Example 3272-((1S)-7-(Methylamino)-7-oxo-1-{[(1-pyridin-2-ylpiperidin-3-yl)carbonyl]amino}heptyl)-5-(2-naphthyl)-1H-imidazol-3-iumtrifluoroacetate (BBB1) Step 1: Benzyl{(1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazol-2-yl]-7-oxoheptyl}carbamate(BBB1)

Example 325, ZZ4 (1 eq.) was dissolved in DMF and HATU (2 eq.) and DIPEA(2 eq.) were added and the mixture was stirred 1 h at RT. A solution ofMeNH₂ in THF (2 N, 5 eq.) was added and after stirring 3 h at RTsolvents were removed under reduced pressure. The crude was used as suchin the following reaction. MS (ES) C₂₉H₃₂N₄O₃ requires: 484, found: 485(M+H)⁺.

Step 2:(7S)-7-Amino-N-methyl-7-[5-(2-naphthyl)-1H-imidazol-2-yl]heptanamide(BBB2)

A solution of the amide (BBB1) (1 eq.) in MeOH was cooled at 0° C. underN₂, then Pd/C (10% wt) was added. After two vacuum-H₂ cycles the mixturewas stirred 2.5 hr under an H₂ atmosphere. The catalyst was filtered offand washed with MeOH then the solvent was removed under reducedpressure. The crude was used as such in the following reaction. MS (ES)C₂₁H₂₆N₄O requires: 350, found: 351 (M+H)⁺.

Step 3:2-((1S)-7-(Methylamino)-7-oxo-1-{[(1-pyridin-2-ylpiperidin-3-yl)carbonyl]amino}heptyl)-5-(2-naphthyl)-1H-imidazol-3-iumtrifluoroacetate (BBB3)

1-Pyridin-2-ylpiperidine-3-carboxylic acid (1.1 eq.) was suspended inDCM and DIPEA (1.1 eq.) and HATU (1.1 eq.) were added and the mixturewas stirred at RT for 1 hour. A solution of the above amine (BBB2) inDMF (0.1 M solution) was added and stirred overnight. The crude wasdirectly purified by preparative RP-HPLC, using H₂O (0.1% TFA) and MeCN(+0.1% TFA) as eluents (column: C18). The desired fractions werelyophilized to afford the titled compound as a white solid. ¹H NMR (400MHz, DMSO-d6) δ: 8.72-8.64 (1H, m), 8.36 (1H, s), 8.20-8.14 (1H, m),8.11-8.01 (2H, m), 8.01-7.88 (3H, m), 7.80-7.65 (2H, m), 7.64-7.56 (2H,m), 7.19-7.08 (1H, m), 6.80-6.71 (1H, m), 5.08-4.98 (1H, m), 4.28-4.20(2H, m), 4.14-4.02 (2H, m), 3.23-2.98 (2H, m), 2.54 (3H, d, J=7.3 Hz),2.04 (2H, t, J=7.2 Hz), 1.99-1.88 (2H, m), 1.82-1.60 (2H, m), 1.57-1.44(3H, m), 1.42-1.21 (4H, m). MS (ES) C₃₂H₃₈N₆O₂ requires: 538, found: 538(M+H)⁺.

Example 3282-[(1S)-1-{[(Benzylamino)carbonyl]amino}-7-(methylamino)-7-oxoheptyl]-5-(2-naphthyl)-1H-imidazol-3-iumtrifluoroacetate (CCC1)

The amine from Example 327, BB2 (1 eq.) was dissolved in DCM, then DIPEA(1 eq.) and benzyl isocyanate were added. After stirring for 1 hr at RTthe solvent were removed under reduced pressure and the crude waspurified by preparative RP-HPLC, using H₂O (0.1% TFA) and MeCN (+0.1%TFA) as eluents (column: C18). The desired fractions were lyophilized toafford the titled compound as a white solid. ¹H NMR (400 MHz, DMSO-d6)δ: 8.36 (1H, s), 8.16 (1H, s), 8.07 (1H, d, J=8.6 Hz), 8.02-7.93 (2H,m), 7.91 (1H, dd, J=8.6 Hz, J₂=1.5 Hz), 7.71-7.55 (3H, m), 7.35-7.19(5H, m), 6.75-6.67 (2H, m), 4.97-4.87 (1H, m), 4.30-4.15 (2H, m), 2.53(3H, d, J=4.6 Hz), 2.04 (2H, t, J=7.4 Hz), 1.97-1.83 (2H, m), 1.55-1.44(2H, m), 1.42-1.22 (4H, m). MS (ES) C₂₉H₃₃N₅O₂ requires: 483, found: 484(M+H)⁺.

Example 3295-(2-Methoxyquinolin-3-yl)-2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-3-ium-L-tartrate(DDD1)

Example 305 was partitioned between EtOAc and saturated aqueous NaHCO₃solution. The aqueous phase was further extracted with EtOAc and thecombined organic phases were dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The remaining colourless oil was dissolved in amixture of H₂O and MeCN and L-tartaric acid (1 eq.) was added. Themixture was lyophilized to afford a white powder. ¹H NMR (400 MHz,DMSO-d6) δ: 12.16 (1H, br. s), 8.71 (1H, br. s), 8.52 (1H, d, J=8.2 Hz),8.13 (1H, d, J=7.7 Hz), 7.84 (1H, d, J=8.2 Hz), 7.66-7.54 (2H, m), 7.42(1H, m), 5.05-4.91 (1H, m), 4.13 (3H, s), 4.04 (2H, s), 3.99-3.85 (2H,m), 3.81-3.65 (2H, m), 3.54-3.37 (1H, m), 2.59 (3H, s), 2.44-2.32 (4H,m), 2.04-1.66 (2H, m), 1.54-1.38 (2H, m), 1.36-1.16 (4H, m), 0.89 (3H,t, J=7.2 Hz). MS (ES) C₂₇H₃₅N₅O₃ requires: 477, found: 478 (M+H⁺).

Procedure [M + H]⁺ M from Example Example Name Observed Expected Number330 2-((1S)-1-{[(1-methyl-1H-indol-3- 443 442 1yl)carbonyl]amino}-7-oxooctyl)-5-phenyl- 1H-imidazol-3-iumtrifluoroacetate 331 2-((1S)-1-{[(5-methoxy-1H-indol-2- 459 458 1yl)carbonyl]amino}-7-oxooctyl)-5-phenyl- 1H-imidazol-3-iumtrifluoroacetate 332 2-((1S)-1-{[(6-fluoro-1H-indol-3- 461 460 1yl)acetyl]amino}-7-oxooctyl)-5-phenyl- 1H-imidazol-3-iumtrifluoroacetate 333 2-((1S)-1-{[(2-methyl-1H-indol-3- 457 456 1yl)acetyl]amino}-7-oxooctyl)-5-phenyl- 1H-imidazol-3-iumtrifluoroacetate 334 2-{(1S)-1-[(1H-indol-3-ylacetyl)amino]-7- 443 442 1oxooctyl}-5-phenyl-1H-imidazol-3-ium trifluoroacetate 3352-{(1S)-1-[(1H-indol-3-ylcarbonyl)amino]- 429 428 17-oxooctyl}-5-phenyl-1H-imidazol-3-ium trifluoroacetate 3362-((1S)-1-{[(5-bromo-1H-indol-3- 521 520 1yl)acetyl]amino}-7-oxooctyl)-5-phenyl- 523 522 1H-imidazol-3-iumtrifluoroacetate 337 2-((1S)-1-{[(7-methoxy-6,7-dihydro-1- 460 461 1benzofuran-2-yl)carbonyl]amino}-7- oxooctyl)-5-phenyl-1H-imidazol-3-iumtrifluoroacetate 338 2-{(1S)-1-[(1-naphthylacetyl)amino]-7- 454 453 1oxooctyl}-5-phenyl-1H-imidazol-3-ium trifluoroacetate 3392-((1S)-1-{[(5-fluoro-1H-indol-3- 461 460 1yl)acetyl]amino}-7-oxooctyl)-5-phenyl- 1H-imidazol-3-iumtrifluoroacetate 340 2-((1S)-1-{[(5-chloro-1H-indol-3- 477 477 1yl)acetyl]amino}-7-oxooctyl)-5-phenyl- 1H-imidazol-3-iumtrifluoroacetate 341 2-{(1S)-1-[(1H-indol-2- 429 428 1ylcarbonyl)amino]-7-oxooctyl}-5-phenyl- 1H-imidazol-3-iumtrifluoroacetate 342 2-((1S)-1-{[(5-fluoro-1H-indol-2- 448 446 1yl)carbonyl]amino}-7-oxooctyl)-5-phenyl- 1H-imidazol-3-iumtrifluoroacetate 343 2-((1S)-1-{[(5-methoxy-1H-indol-3- 473 472 1yl)acetyl]amino}-7-oxooctyl)-5-phenyl- 1H-imidazol-3-iumtrifluoroacetate 344 2-((1S)-1-{[(5-hydroxy-1H-indol-3- 459 458 1yl)acetyl]amino}-7-oxooctyl)-5-phenyl- 1H-imidazol-3-iumtrifluoroacetate 345 2-((1S)-1-{[(6-methoxy-2-oxo-2,3- 489 488 1dihydro-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium trifluoroacetate 3462-((1S)-1-{[(5-methoxy-2-oxo-2,3 - 489 488 1dihydro-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-3-ium trifluoroacetate 3476-(2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H- 446 445 1 imidazol-3-ium-2-yl)octyl]amino}ethyl)[1,2,4]triazolo[1,5- a]pyrimidin-3-iumbis(trifluoroacetate) 348 3-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol- 515514 1 3-ium-2-yl)octyl]amino}carbonyl)-3,4-dihydrospiro[isochromene-1,4′- piperidinium] bis(trifluoroacetate) 3494-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol- 515 514 13-ium-2-yl)octyl]amino}carbonyl)-3,4-dihydrospiro[chromene-2,4′-piperidinium] bis(trifluoroacetate) 3505-chloro-2-(2-oxo-2-{[(1S)-7-oxo-1-(5- 478 477 1phenyl-1H-imidazol-3-ium-2- yl)octyl]amino}ethyl)-1H-3,1-benzimidazol-3-ium bis(trifluoroacetate) 3512-((1S)-7-oxo-1-{[(2-oxoquinazolin- 472 471 11(2H)-yl)acetyl]amino}octyl)-5-phenyl- 1H-imidazol-3-iumtrifluoroacetate 352 2-((1S)-7-oxo-1-{[(2-oxo-1,3-benzoxazol- 461 460 13(2H)-yl)acetyl]amino}octyl)-5-phenyl- 1H-imidazol-3-iumtrifluoroacetate 353 2-{(1S)-1-[(2H-indazol-2-ylacetyl)amino]- 444 443 17-oxooctyl}-5-phenyl-1H-imidazol-3-ium trifluoroacetate 3543-({[(1S)-7-oxo-1-(5-phenyl-1H-imidazol- 499 498 13-ium-2-yl)octyl]amino}carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidinium] bis(trifluoroacetate) 3552-((1S)-7-oxo-1-{[(2-oxo-1,2,3,4- 459 458 1 tetrahydroquinolin-4-yl)carbonyl]amino}octyl)-5-phenyl-1H- imidazol-3-ium trifluoroacetate356 2-((1S)-1-{[(5-cyano-1H-indol-1- 468 467 1yl)acetyl]amino}-7-oxooctyl)-5-phenyl- 1H-imidazol-3-iumtrifluoroacetate 357 2-{(1S)-1-[(2-naphthylacetyl)amino]-7- 454 453 1oxooctyl}-5-phenyl-1H-imidazol-3-ium trifluoroacetate 3582-((1S)-1-{[(5-chloro-1-benzothien-3- 494 494 1yl)acetyl]amino}-7-oxooctyl)-5-phenyl- 1H-imidazol-3-iumtrifluoroacetate 359 2-((1S)-1-{[(5-chloro-1H-indazol-3- 478 477 1yl)acetyl]amino}-7-oxooctyl)-5-phenyl- 1H-imidazol-3-iumtrifluoroacetate 360 2-(2-{(1S)-1-[(1-Azoniabicyclo[2.2.2]oct- 518 517307 4-ylcarbonyl)amino]-7-oxononyl}-1H- imidazol-1-ium-5-yl)-4-methoxyquinolinium tris(trifluoroacetate) 3614-Methoxy-2-[2-((1S)-1-{[(5-methoxy-2- 582 581 307methyl-1H-indol-3-yl)acetyl]amino}-7- oxononyl)-1H-imidazol-1-ium-5-yl]quinolinium bis(trifluoroacetate) 3625-Methoxy-N-{(1S)-1-[5-(2-naphthyl)-1,3- 524 523 137oxazol-2-yl]-7-oxononyl}-1H-indole-2- carboxamide 3631-Methyl-4-[({(1S)-1-[5-(2-naphthyl)-1,3- 476 475 137 oxazol-2-yl]-7-oxononyl}amino)carbonyl]piperidinium trifluoroacetate 3644-[({(1S)-1-[5-(2-Naphthyl)-1,3-oxazol-2- 488 487 137yl]-7-oxononyl}amino)carbonyl]-1- azoniabicyclo[2.2.2]octanetrifluoroacetate 365 N,N,2-Trimethyl-1-({(1S)-1-[5-(2- 464 463 137naphthyl)-1,3-oxazol-2-yl]-7- oxononyl}amino)-1-oxopropan-2-aminiumtrifluoroacetate 366 1-Methyl-3-[({(1S)-1-[5-(2-naphthyl)-1,3- 448 447137 oxazol-2-yl]-7- oxononyl}amino)carbonyl]azetidinium trifluoroacetate367 N-{(1S)-1-[5-(2-Naphthyl)-1,3-oxazol-2- 393 392 137yl]-7-oxononyl}acetamide 368 N,N-Dimethyl-N′-{(1S)-1-[5-(2-naphthyl)-450 449 137 1,3-oxazol-2-yl]-7- oxononyl}ethanediamide 3698-[2-(1-{[(1-Methylpiperidinium-4- 476 475 1yl)carbonyl]amino}-7-oxononyl)-1H- imidazol-1-ium-5-yl]quinoliniumtris(trifluoroacetate) 370 2-((1S)-1-{[(1-Methylpiperidinium-4- 436 435140 yl)carbonyl]amino}-7-oxononyl)-6- phenylpyridiniumbis(trifluoroacetate) 371 N-{(1S)-1-[5-(2-Naphthyl)-1,3-oxazol-2- 537536 137 yl]-7-oxononyl}-2-(2-oxoquinazolin- 1(2H)-yl)acetamide 3723-(2-Ethyl-1H-benzimidazol-1-yl)-N- 551 550 137{(1S)-1-[5-(2-naphthyl)-1,3-oxazol-2-yl]- 7-oxononyl}propanamide 373N,N-Dimethyl-2-({(1S)-1-[5-(2-naphthyl)- 436 435 1371,3-oxazol-2-yl]-7-oxononyl}amino)-2- oxoethanaminium trifluoroacetate374 2-Ethyl-1-(3-oxo-3-{[(1S)-7-oxo-1-(6- 511 510 140phenylpyridinium-2- yl)nonyl]amino}propyl)-1H-3,1- benzimidazol-1-iumbis(trifluoroacetate) 375 4-({[(1S)-7-Oxo-1-(6-phenylpyridinium-2- 448447 140 yl)nonyl]amino}carbonyl)-1- azoniabicyclo[2.2.2]octanebis(trifluoroacetate) 376 2-((1S)-1- 444 443 140{[(Benzylamino)carbonyl]amino}-7- oxononyl)-6-phenylpyridiniumtrifluoroacetate 377 2-((1S)-7-[Methoxy(methyl)amino]-1- 532 531 108{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-phenyl- 1H-imidazol-1-iumtrifluoroacetate 378 2-((1S)-1-{[(5-Methoxy-2-methyl-1H- 553 552 1indol-3-yl)acetyl]amino}-7-oxononyl)-5-quinoxalin-2-yl-1H-imidazol-1-ium trifluoroacetate 3792-((1S)-1-{[(5-Methoxy-2-methyl-1H- 581 580 1indol-3-yl)acetyl]amino}-7-oxononyl)-5-(3-methoxy-2-naphthyl)-1H-imidazol-1- ium trifluoroacetate 3805-{[Benzyl(methyl)ammonio]methyl}-2- 558 557 311(1-{[(5-methoxy-2-methyl-1H-indol-3- yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium bis(trifluoroacetate) 3812-{[2-(1-{[(5-Methoxy-2-methyl-1H- 570 569 311indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]methyl}-1,2,3,4- tetrahydroisoquinoliniumbis(trifluoroacetate) 382 2-((1S)-1-{[(5-Methoxy-2-methyl-1H- 515 514316 indol-3-yl)acetyl]amino}-7-oxodecyl)-5- phenyl-1H-imidazol-1-iumtrifluoroacetate 383 2-(1-{[(5-Methoxy-2-methyl-1H-indol-3- 531 530 304yl)acetyl]amino}-7-oxononyl)-5-(2- methoxyphenyl)-1H-imidazol-3-iumtrifluoroacetate 384 2-(1-{[(5-Methoxy-2-methyl-1H-indol-3- 531 530 304yl)acetyl]amino}-7-oxononyl)-5-(3- methoxyphenyl)-1H-imidazol-3-iumtrifluoroacetate 385 6-[2-(1-{[(5-Methoxy-2-methyl-1H-indol- 552 551 3043-yl)acetyl]amino}-7-oxononyl)-1H- imidazol-3-ium-5-yl]quinoliniumbis(trifluoroacetate) 386 5-[2-(1-{[(5-Methoxy-2-methyl-1H-indol- 566565 304 3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium-5-yl]-2-methylquinolinium bis(trifluoroacetate) 3875-[2-(1-{[(5-Methoxy-2-methyl-1H-indol- 552 551 3043-yl)acetyl]amino}-7-oxononyl)-1H- imidazol-3-ium-5-yl]quinoliniumbis(trifluoroacetate) 388 5-[2-(1-{[(5-Methoxy-2-methyl-1H-indol- 566565 304 3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium-5-yl]-8-methylquinolinium bis(trifluoroacetate) 3898-Methoxy-5-[2-(1-{[(5-methoxy-2- 582 581 304methyl-1H-indol-3-yl)acetyl]amino}-7- oxononyl)-1H-imidazol-3-ium-5-yl]quinolinium bis(trifluoroacetate) 3905-(1-Benzothien-7-yl)-2-(1-{[(5-methoxy- 557 556 3042-methyl-1H-indol-3-yl)acetyl]amino}-7- oxononyl)-1H-imidazol-3-iumtrifluoroacetate 391 5-(1H-Indol-5-yl)-2-(1-{[(5-methoxy-2- 540 539 304methyl-1H-indol-3-yl)acetyl]amino}-7- oxononyl)-1H-imidazol-3-iumtrifluoroacetate 392 5-[3-(3,5-Dimethyl-1H-pyrazol-1- 595 594 304yl)phenyl]-2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)- 1H-imidazol-3-iumtrifluoroacetate 393 5-(3-Methoxy-2-naphthyl)-2-((1S)-1-{[(1- 477 476 1methylazetidinium-3-yl)carbonyl]amino}- 7-oxononyl)-1H-imidazol-1-iumbis(trifluoroacetate) 394 2-((1S)-1-{[(2-Ethyl-5-methyl-1H-indol-3- 499498 1 yl)acetyl]amino}-7-oxononyl)-5-phenyl- 1H-imidazol-1-iumtrifluoroacetate 395 2-((1S)-1-{[(1-Methylazetidinium-3- 449 448 1yl)carbonyl]amino}-7-oxononyl)-5- quinoxalin-2-yl-1H-imidazol-1-iumbis(trifluoroacetate) 396 2-((1S)-1-{[(2-Ethyl-6-methyl-1H-indol-3- 499498 1 yl)acetyl]amino}-7-oxononyl)-5-phenyl- 1H-imidazol-1-iumtrifluoroacetate 397 5-[4-(Dimethylammonio)phenyl]-2--1- 544 543 304{[(5-methoxy-2-methyl-1H-indol-3- yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium bis(trifluoroacetate) 3985-(2-Fluoro-4-methoxyphenyl)-2-(1-{[(5- 549 548 304methoxy-2-methyl-1H-indol-3- yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium trifluoroacetate 3995-(3-Fluoro-4-methoxyphenyl)-2-(1-{[(5- 549 548 304methoxy-2-methyl-1H-indol-3- yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium trifluoroacetate 4005-(3-Carboxyphenyl)-2-(1-{[(5-methoxy- 545 544 3042-methyl-1H-indol-3-yl)acetyl]amino}-7- oxononyl)-1H-imidazol-1-iumtrifluoroacetate 401 5-Biphenyl-2-yl-2-(1-{[(5-methoxy-2- 577 576 304methyl-1H-indol-3-yl)acetyl]amino}-7- oxononyl)-1H-imidazol-1-iumtrifluoroacetate 402 5-Dibenzo[b,d]furan-4-yl-2-(1-{[(5- 591 590 304methoxy-2-methyl-1H-indol-3- yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium trifluoroacetate 4032-(1-{[(5-Methoxy-2-methyl-1H-indol-3- 612 611 304yl)acetyl]amino}-7-oxononyl)-5-[3- (piperidin-1-ylcarbonyl)phenyl]-1H-imidazol-1-ium trifluoroacetate 4042-(1-{[(5-Methoxy-2-methyl-1H-indol-3- 553 552 304yl)acetyl]amino}-7-oxononyl)-5- quinoxalin-6-yl-1H-imidazol-1-iumtrifluoroacetate 405 5-[(Dimethylammonio)methyl]-2-(1-{[(5- 482 481 311methoxy-2-methyl-1H-indol-3- yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium bis(trifluoroacetate) 4065-(1,4-Dimethoxy-2-naphthyl)-2-((1S)-1- 611 610 1{[(5-methoxy-2-methyl-1H-indol-3- yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium trifluoroacetate 407 2-((1S)-1-{[(5-Methoxy-2-methyl-1H-613 611 108 indol-3-yl)acetyl]amino}-7-{[2-(methylthio)ethyl]amino}-7-oxoheptyl)-5- (2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate 408 2-((1S)-7-(Methoxyamino)-1-{[(5- 569 567 108methoxy-2-methyl-1H-indol-3- yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-ium trifluoroacetate 4092-((1S)-7-(Ethoxyamino)-1-{[(5-methoxy- 583 581 1082-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1- ium trifluoroacetate 4102-((1S)-1-{[(2-Methyl-5-nitro-1H-indol-3- 516 515 1yl)acetyl]amino}-7-oxononyl)-5-phenyl- 1H-imidazol-1-iumtrifluoroacetate 411 2-((1S)-1-{[(5-Methoxy-2-methyl-1H- 500 499 1inden-3-yl)acetyl]amino}-7-oxononyl)-5- phenyl-1H-imidazol-1-iumtrifluoroacetate 412 2-((1S)-1-{[(5-Hydroxy-2-methyl-1H- 487 486 1indol-3-yl)acetyl]amino}-7-oxononyl)-5- phenyl-1H-imidazol-1-iumtrifluoroacetate 413 2-((1S)-1-{[3-(5-Methoxy-1H- 502 501 1benzimidazol-2-yl)propanoyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 4142-{(1S)-1-[(1-Benzothien-3- 474 473 1ylacetyl)amino]-7-oxononyl}-5-phenyl- 1H-imidazol-1-ium trifluoroacetate415 2-((1S)-1-{[(2,5-Dimethyl-1H-indol-3- 485 484 1yl)acetyl]amino}-7-oxononyl)-5-phenyl- 1H-imidazol-1-iumtrifluoroacetate 416 2-((1S)-1-{[3-(1H-Benzimidazol-2- 472 471 1yl)propanoyl]amino}-7-oxononyl)-5- phenyl-1H-imidazol-1-iumtrifluoroacetate 417 2-((1S)-1-{[(6-Methoxy-1H-indol-3- 487 486 1yl)acetyl]amino}-7-oxononyl)-5-phenyl- 1H-imidazol-1-iumtrifluoroacetate 418 2-{(1S)-1-[(1H-Indol-6-ylacetyl)amino]-7- 457 456 1oxononyl}-5-phenyl-1H-imidazol-1-ium trifluoroacetate 4192-((1S)-1-{[(2-Methyl-1,3-benzothiazol-5- 489 488 1yl)acetyl]amino}-7-oxononyl)-5-phenyl- 1H-imidazol-1-iumtrifluoroacetate 420 2-((1S)-1-{[3-(5-Methoxy-2-oxo-1,3- 519 518 1benzoxazol-3(2H)-yl)propanoyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 4212-((1S)-1-{[3-(7-Methoxy-1H-indol-3- 501 500 1yl)propanoyl]amino}-7-oxononyl)-5- phenyl-1H-imidazol-1-iumtrifluoroacetate 422 2-((1S)-1-{[3-(1,3-Benzothiazol-2- 489 488 1yl)propanoyl]amino}-7-oxononyl)-5- phenyl-1H-imidazol-1-iumtrifluoroacetate 423 2-((1S)-1-{[(5-Methoxy-2-oxo-2,3- 503 502 1dihydro-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 4242-((1S)-1-{[(6-Methoxy-2-oxo-2,3- 503 502 1dihydro-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 425 2-((1S)-1- 444443 140 {[(Benzylamino)carbonyl]amino}-7- oxononyl)-4-phenylpyridiniumtrifluoroacetate 426 4-({[(1S)-7-Oxo-1-(4-phenylpyridinium-2- 448 447140 yl)nonyl]amino}carbonyl)-1- azoniabicyclo[2.2.2]octanebis(trifluoroacetate) 427 2-((1S)-1-{[2-(Dimethylammonio)-2- 424 423 140methylpropanoyl]amino}-7-oxononyl)-4- phenylpyridiniumbis(trifluoroacetate) 428 5-(3,5-Dimethoxy-2-naphthyl)-2-((1S)-1- 611610 1 {[(5-methoxy-2-methyl-1H-indol-3- yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium trifluoroacetate 4292-((1S)-1-{[(Benzyloxy)carbonyl]amino}- 445 444 1407-oxononyl)-4-phenylpyridinium trifluoroacetate 4302-((1S)-1-{[(1-Methyl-1H-indol-3- 471 470 1yl)acetyl]amino}-7-oxononyl)-5-phenyl- 1H-imidazol-1-iumtrifluoroacetate 431 2-((1S)-1-{[(7-Fluoro-2-methyl-1H-indol- 489 488 13-yl)acetyl]amino}-7-oxononyl)-5-phenyl- 1H-imidazol-1-iumtrifluoroacetate 432 2-((1S)-1-{[(5-Ethyl-2-methyl-1H-indol-3- 499 498 1yl)acetyl]amino}-7-oxononyl)-5-phenyl- 1H-imidazol-1-iumtrifluoroacetate 433 2-(5-tert-Butyl-2-methyl-1H-indol-3-yl)- 527 526 1N-[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-2- yl)nonyl]acetamide 4342-((1S)-1-{[(5-Ethoxy-2-methyl-1H-indol- 515 514 13-yl)acetyl]amino}-7-oxononyl)-5-phenyl- 1H-imidazol-1-iumtrifluoroacetate 435 2-[5-(Benzyloxy)-2-methyl-1H-indol-3- 577 576 1yl]-N-[(1S)-7-oxo-1-(5-phenyl-1H- imidazol-2-yl)nonyl]acetamide 4363-(1H-Indol-1-yl)-N-[(1S)-7-oxo-1-(5- 471 470 1 phenyl-1H-imidazol-2-yl)nonyl]propanamide 437 2-((1S)-1-{[(5-Methoxy-1H-indol-3- 487 486 1yl)acetyl]amino}-7-oxononyl)-5-phenyl- 1H-imidazol-1-iumtrifluoroacetate 438 2-((1S)-7-Oxo-1-{[3-(2-oxo-1,3- 505 504 1benzothiazol-3(2H)- yl)propanoyl]amino}nonyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 439 2-{(1S)-7-Oxo-1-[(quinolin-3- 469468 1 ylacetyl)amino]nonyl}-5-phenyl-1H- imidazol-1-ium trifluoroacetate440 2-{(1S)-7-Oxo-1-[(quinolin-5- 469 468 1ylacetyl)amino]nonyl}-5-phenyl-1H- imidazol-1-ium trifluoroacetate 4412-((1S)-1-{[3-(6-Chloro-1H-benzimidazol- 507 506 12-yl)propanoyl]amino}-7-oxononyl)-5- 509 508 phenyl-1H-imidazol-1-iumtrifluoroacetate 442 2-((1S)-1-{[3-(6-Fluoro-1H-benzimidazol- 490 489 12-yl)propanoyl]amino}-7-oxononyl)-5- phenyl-1H-imidazol-1-iumtrifluoroacetate 443 N-[(1S)-7-Oxo-1-(5-phenyl-1H-imidazol- 472 471 12-yl)nonyl]-2-(5,6,7,8- tetrahydronaphthalen-1-yl)acetamide 4442-((1S)-1-{[(5-Methoxy-2-methyl-1H- 515 514 316indol-3-yl)acetyl]amino}-8-methyl-7-oxononyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 4452-((1S)-6-Carboxy-1-{[(5-methoxy-2- 409 488 107 methyl-1H-indol-3-yl)acetyl]amino}hexyl)-5-phenyl-1H- imidazol-1-ium trifluoroacetate 4462-((1S)-1-{[(5-Methoxy-2-methyl-1H- 507 506 304indol-3-yl)acetyl]amino}-7-oxononyl)-5- (2-thienyl)-1H-imidazol-3-iumtrifluoroacetate 447 2-((1S)-1-{[(5-Methoxy-2-methyl-1H- 551 550 304indol-3-yl)acetyl]amino}-7-oxononyl)-5- (1-naphthyl)-1H-imidazol-3-iumtrifluoroacetate 448 2-((1S)-1-{[(5-Methoxy-2-methyl-1H- 552 551 304indol-3-yl)acetyl]amino}-7-oxononyl)-5- quinolin-8-yl-1H-imidazol-3-iumtrifluoroacetate 449 2-((1S)-1-{[(5-Methoxy-2-methyl-1H- 586 585 304indol-3-yl)acetyl]amino}-7-oxononyl)-5-(2-morpholin-4-ylphenyl)-1H-imidazol-3- ium trifluoroacetate 4502-((1S)-1-{[(5-Methoxy-2-methyl-1H- 546 545 304indol-3-yl)acetyl]amino}-7-oxononyl)-5-(3-nitrophenyl)-1H-imidazol-3-ium trifluoroacetate 4513-[2-((1S)-1-{[(5-Methoxy-2-methyl-1H- 502 501 304indol-3-yl)acetyl]amino}-7-oxononyl)-1H- imidazol-3-ium-5-yl]pyridiniumbis(trifluoroacetate) 452 5-(3-Cyanophenyl)-2-((1S)-1-{[(5- 526 525 304methoxy-2-methyl-1H-indol-3- yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium trifluoroacetate 453 2-((1S)-1-{[(5-Methoxy-2-methyl-1H-585 584 304 indol-3-yl)acetyl]amino}-7-oxononyl)-5-[3-(trifluoromethoxy)phenyl]-1H- imidazol-3-ium trifluoroacetate 4542-((1S)-1-{[(5-Methoxy-2-methyl-1H- 585 584 304indol-3-yl)acetyl]amino}-7-oxononyl)-5- [4-(trifluoromethoxy)phenyl]-1H-imidazol-3-ium trifluoroacetate 455 2-((1S)-1-{[(5-Methoxy-2-methyl-1H-569 568 304 indol-3-yl)acetyl]amino}-7-oxononyl)-5-[4-(trifluoromethyl)phenyl]-1H-imidazol- 3-ium trifluoroacetate 4562-((1S)-1-{[(5-Methoxy-2-methyl-1H- 569 568 304indol-3-yl)acetyl]amino}-7-oxononyl)-5-[3-(trifluoromethyl)phenyl]-1H-imidazol- 3-ium trifluoroacetate 4572-((1S)-1-{[(5-Methoxy-2-methyl-1H- 569 568 304indol-3-yl)acetyl]amino}-7-oxononyl)-5-[2-(trifluoromethyl)phenyl]-1H-imidazol- 3-ium trifluoroacetate 4582-((1S)-1-{[(5-Methoxy-2-methyl-1H- 519 518 304indol-3-yl)acetyl]amino}-7-oxononyl)-5-[2-fluoro-phenyl]-1H-imidazol-3-ium trifluoroacetate 4592-((1S)-1-{[(5-Methoxy-2-methyl-1H- 545 544 304indol-3-yl)acetyl]amino}-7-oxononyl)-5-[3-(ethoxy)phenyl]-1H-imidazol-3-ium trifluoroacetate 4602-((1S)-1-{[(5-Methoxy-2-methyl-1H- 545 544 304indol-3-yl)acetyl]amino}-7-oxononyl)-5-[4-(ethoxy)phenyl]-1H-imidazol-3-ium trifluoroacetate 4615-[4-(Acetylamino)phenyl]-2-((1S)-1-{[(5- 558 557 304methoxy-2-methyl-1H-indol-3- yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium trifluoroacetate 4625-[2-(Methoxycarbonyl)phenyl]-2-((1S)-1- 559 558 304{[(5-methoxy-2-methyl-1H-indol-3- yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium trifluoroacetate 463 2-((1S)-1-{[(5-Methoxy-2-methyl-1H-526 525 304 indol-3-yl)acetyl]amino}-7-oxononyl)-5-[4-cyano-phenyl]-1H-imidazol-3-ium trifluoroacetate 4642-((1S)-1-{[5-(3-Methyl-5,6,7,8- 530 529 1tetrahydro-1,8-naphthyridin-2- yl)pentanoyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 4656-(2-Oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H- 464 463 1 imidazol-1-ium-2-yl)nonyl]amino}ethyl)imidazo[2,1- b][1,3]thiazol-4-iumbis(trifluoroacetate) 466 2-{(1S)-1-[(1-Benzofuran-5- 458 457 1ylacetyl)amino]-7-oxononyl}-5-phenyl- 1H-imidazol-1-ium trifluoroacetate467 2-{(1S)-1-[(1-Benzothien-2- 474 473 1ylacetyl)amino]-7-oxononyl}-5-phenyl- 1H-imidazol-1-ium trifluoroacetate468 2-((1S)-1-{[(2-Ethyl-1H-benzimidazol-1- 486 485 1yl)acetyl]amino}-7-oxononyl)-5-phenyl- 1H-imidazol-1-iumtrifluoroacetate 469 2-(1-{[(5-methoxy-2-methyl-1H-indol-3- 425 424 304yl)acetyl]amino}-7-oxononyl)-1H- then imidazol-1-ium trifluoroacetatehydrogenated 470 2-[2-((1S)-1-{[3- 480 479 307(Dimethylammonio)propanoyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]-4- methoxyquinoliniumtris(trifluoroacetate) 471 5-(4-Chlorophenyl)-2-((1S)-1-{[(5- 535 534 1methoxy-2-methyl-1H-indol-3- 537 536 yl)acetyl]amino}-7-oxononyl)-1H-539 538 imidazol-1-ium trifluoroacetate 4725-(3,4-Dichlorophenyl)-2-((1S)-1-{[(5- 569 568 1methoxy-2-methyl-1H-indol-3- 571 570 yl)acetyl]amino}-7-oxononyl)-1H-573 572 imidazol-1-ium trifluoroacetate 4735-(3-Bromophenyl)-2-((1S)-1-{[(5- 579 578 1 methoxy-2-methyl-1H-indol-3-581 580 yl)acetyl]amino}-7-oxononyl)-1H- imidazol-1-ium trifluoroacetate474 2-((1S)-7-Methoxy-1-{[(5-methoxy-2- 504 503 107methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 4752-(1-{[(5-Methoxy-2-methyl-1H-indol-3- 529 528 315yl)acetyl]amino}-7-oxononyl)-5-(2- phenylethyl)-1H-imidazol-1-iumtrifluoroacetate 476 7-(3-Oxo-3-{[(1S)-7-oxo-1-(5-phenyl-1H- 484 483 1imidazol-1-ium-2-yl)nonyl]amino}propyl)- 1,8-naphthyridin-1-iumbis(trifluoroacetate) 477 7-(3-Oxo-3-{[(1S)-7-oxo-1-(5-phenyl-1H- 488487 1 imidazol-1-ium-2-yl)nonyl]amino}propyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-1-ium bis(trifluoroacetate) 478N³,N³-Dimethyl-N-[{(1S)-1-[5-(2- 451 450 308naphthyl)-1,3,4-oxadiazol-2-yl]-7- oxononyl}-α-alaninamide 4792-{(1S)-7-Oxo-1-[(4,5,6,7-tetrahydro-1H- 448 447 1indazol-3-ylcarbonyl)amino]nonyl}-5- phenyl-1H-imidazol-1-iumtrifluoroacetate 480 2-{(1S)-7-Oxo-1-[(4,5,6,7-tetrahydro-1- 464 463 1benzothien-3-ylcarbonyl)amino]nonyl}-5- phenyl-1H-imidazol-1-iumtrifluoroacetate 481 2-((1S)-7-Oxo-1-{[3-(1-oxo-1,3-dihydro- 487 486 12H-isoindol-2-yl)propanoyl]amino}nonyl)- 5-phenyl-1H-imidazol-1-iumtrifluoroacetate 482 2-{(1S)-1-[({2-[2- 530 529 1(Dimethylammonio)ethyl]-3-oxo-2,3- dihydro-1H-isoindol-4-yl}carbonyl)amino]-7-oxononyl}-5- phenyl-1H-imidazol-1-iumbis(trifluoroacetate) 483 6-Benzyl-2-oxo-3-({[(1S)-7-oxo-1-(5- 566 565 1phenyl-1H-imidazol-1-ium-2- yl)nonyl]amino}carbonyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridin-6-ium bis(trifluoroacetate) 4847-(4-Oxo-4-{[(1S)-7-oxo-1-(5-phenyl-1H- 567 566 1 imidazol-1-ium-2-yl)nonyl]amino}butanoyl)-6,7,8,9-tetrahydropyrido[2,3-b]-1,6-naphthyridin- 1-ium bis(trifluoroacetate)485 2-((1S)-1-{[(2-Acetyl-1,2,3,4- 515 514 1tetrahydroisoquinolin-1-yl)acetyl]amino}-7-oxononyl)-5-phenyl-1H-imidazol-1-ium trifluoroacetate 4862-Methyl-3-({[(1S)-7-oxo-1-(5-phenyl-1H- 473 472 1 imidazol-1-ium-2-yl)nonyl]amino}carbonyl)-1,2,3,4- tetrahydroisoquinoliniumbis(trifluoroacetate) 487 2-(2-Oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H- 473472 1 imidazol-1-ium-2-yl)nonyl]amino}ethyl)-1,2,3,4-tetrahydroisoquinolinium bis(trifluoroacetate) 4884-[2-((1S)-1-{[(5-Methoxy-2-methyl-1H- 502 501 304indol-3-yl)acetyl]amino}-7-oxononyl)-1H- imidazol-3-ium-5-yl]pyridiniumbis(trifluoroacetate) 489 2-((1S)-1-{[(5-Methoxy-2-methyl-1H- 546 545304 indol-3-yl)acetyl]amino}-7-oxononyl)-5-(2-nitrophenyl)-1H-imidazol-3-ium trifluoroacetate 4905-(3-Ammoniophenyl)-2-((1S)-1-{[(5- 516 515 304methoxy-2-methyl-1H-indol-3- yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium bis(trifluoroacetate) 4915-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2- 559 558 304((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H- imidazol-3-ium trifluoroacetate 4925-(2,4-Dimethoxyphenyl)-2-((1S)-1-{[(5- 561 560 304methoxy-2-methyl-1H-indol-3- yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium trifluoroacetate 4935-[2-Fluoro-5-(trifluoromethyl)phenyl]-2- 587 586 304((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H- imidazol-3-ium trifluoroacetate 4945-[3-(Ammoniomethyl)phenyl]-2-((1S)-1- 530 529 304{[(5-methoxy-2-methyl-1H-indol-3- yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium bis(trifluoroacetate) 4955-[2-(Ammoniomethyl)-4-fluorophenyl]-2- 548 547 304((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H- imidazol-3-ium bis(trifluoroacetate)496 5-Biphenyl-3-yl-2-((1S)-1-{[(5-methoxy- 577 576 3042-methyl-1H-indol-3-yl)acetyl]amino}-7- oxononyl)-1H-imidazol-3-iumtrifluoroacetate 497 3-[2-((1S)-1-{[(5-Methoxy-2-methyl-1H- 552 551 304indol-3-yl)acetyl]amino}-7-oxononyl)-1H- imidazol-3-ium-5-yl]quinoliniumbis(trifluoroacetate) 498 5-(3-Carboxyphenyl)-2-((1S)-1-{[(5- 545 544304 methoxy-2-methyl-1H-indol-3- yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium trifluoroacetate 499 2-((1S)-1-{[(5-Methoxy-2-methyl-1H-569 568 304 indol-3-yl)acetyl]amino}-7-oxononyl)-5-[3-(1H-tetrazol-5-yl)phenyl]-1H-imidazol- 3-ium trifluoroacetate 5002-((1S)-1-{[(5-Methoxy-2-methyl-1H- 622 621 304indol-3-yl)acetyl]amino}-7-oxononyl)-5- (3-{[(methylsulfonyl)amino]carbonyl}phenyl)- 1H-imidazol-3-iumtrifluoroacetate 501 2-((1R)-1-{[(1-Methylazetidinium-3- 447 446 1yl)carbonyl]amino}-7-oxononyl)-5-(2- naphthyl)-1H-imidazo

 l-1-ium bis(trifluoroacetate) 5022-[(1S)-1-({[1-(2-tert-Butoxy-2-oxoethyl)- 615 614 15-methoxy-2-methyl-1H-indol-3- yl]acetyl}amino)-7-oxononyl]-5-phenyl-1H-imidazol-1-ium trifluoroacetate 5032-[(1S)-1-({[5-Methoxy-2-methyl-1- 592 591 1(pyridin-3-ylmethyl)-1H-indol-3- yl]acetyl}amino)-7-oxononyl]-5-phenyl-1H-imidazol-1-ium trifluoroacetate 5042-((1S)-1-{[(5-Methoxy-1,2-dimethyl-1H- 515 514 1indol-3-yl)acetyl]amino}-7-oxononyl)-5- phenyl-1H-imidazol-1-iumtrifluoroacetate 505 2-[(1S)-1-({[5-Methoxy-2-methyl-1-(2- 598 597 1pyrrolidinium-1-ylethyl)-1H-indol-3-yl]acetyl}amino)-7-oxononyl]-5-phenyl- 1H-imidazol-1-iumbis(trifluoroacetate) 506 4-{2-[5-Methoxy-2-methyl-3-(2-oxo-2- 614 613 1{[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)nonyl]amino}ethyl)-1H-indol-1- yl]ethyl}morpholin-4-iumbis(trifluoroacetate) 507 2-((1S)-1-{[(5-Methyl-1,2-benzisoxazol-3- 473472 1 yl)acetyl]amino}-7-oxononyl)-5-phenyl- 1H-imidazol-1-iumtrifluoroacetate 508 2-[(1S)-1-({[5-(Dimethylammonio)-2- 514 513 1methyl-1H-indol-3-yl]acetyl}amino)-7-oxononyl]-5-phenyl-1H-imidazol-1-ium bis(trifluoroacetate) 5091-Methyl-4-[({(1S)-1-[5-(2-naphthyl)-1H- 503 502 316imidazol-1-ium-2-yl]-7- oxoundecyl}amino)carbonyl]piperidiniumbis(trifluoroacetate) 510 1-Methyl-4-[({(1S)-1-[5-(2-naphthyl)-1H- 489488 316 imidazol-1-ium-2-yl]-7- oxodecyl}amino)carbonyl]piperidiniumbis(trifluoroacetate) 511 N-[1-(5-Acetyl-1H-imidazol-2-yl)-7- 467 466314 oxononyl]-2-(5-methoxy-2-methyl-1H- indol-3-yl)acetamide 5122-[2-((1S)-1-{[3- 480 479 307 (Dimethylammonio)propanoyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]-4- methoxyquinolinium trichloride 5132-((1S)-1-{[(6-Methoxy-1-benzofuran-3- 488 487 1yl)acetyl]amino}-7-oxononyl)-5-phenyl- 1H-imidazol-1-iumtrifluoroacetate 514 6-({[(1S)-7-Oxo-1-(5-phenyl-1H-imidazol- 455 454 11-ium-2- yl)nonyl]amino}carbonyl)quinolinium bis(trifluoroacetate) 5156-({[(1S)-7-Oxo-1-(5-phenyl-1H-imidazol- 455 454 1 1-ium-2-yl)nonyl]amino}carbonyl)isoquinolinium bis(trifluoroacetate) 5165-Methyl-6-({[(1S)-7-oxo-1-(5-phenyl-1H- 463 462 1 imidazol-1-ium-2-yl)nonyl]amino}carbonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-3,5- diium tris(trifluoroacetate)517 2-(5-Methyl-1-benzothien-3-yl)-N-[(1S)-7- 488 487 1oxo-1-(5-phenyl-1H-imidazol-2- yl)nonyl]acetamide 5182-[(1S)-1-({[1-(Carboxymethyl)-5- 559 558 1 methoxy-2-methyl-1H-indol-3-yl]acetyl}amino)-7-oxononyl]-5-phenyl- 1H-imidazol-1-iumtrifluoroacetate 519 4-{[5-Methoxy-2-methyl-3-(2-oxo-2- 641 640 1{[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-1-ium-2-yl)nonyl]amino}ethyl)-1H-indol-1-yl]acetyl}-1-methylpiperazin-1-ium bis(trifluoroacetate) 5207-Methyl-2-({[(1S)-7-oxo-1-(5-phenyl-1H- 463 462 1 imidazol-1-ium-2-yl)nonyl]amino}carbonyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-4,7-diium tris(trifluoroacetate) 521 2-{(1S)-1-[({5- 528 527 1[(Dimethylammonio)methyl]-2-methyl-1H-indol-3-yl}acetyl)amino]-7-oxononyl}- 5-phenyl-1H-imidazol-1-iumbis(trifluoroacetate) 522 5-Bromo-2-((1S)-1-{[(5-methoxy-2- 503 502 304methyl-1H-indol-3-yl)acetyl]amino}-7- 505 504 oxononyl)-1H-imidazol

-3-ium trifluoroacetate 523 5-(4-Carboxyphenyl)-2-((1S)-1-{[(5- 544 544304 methoxy-2-methyl-1H-indol-3- yl)acetyl]amino}-7-oxononyl)-1H-imidazol-3-ium trifluoroacetate 524 5-(3-Hydroxyphenyl)-2-((1S)-1-{[(5-517 516 304 methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H- imidazol-1-ium trifluoroacetate 5255-[2-((1S)-1-{[(5-Methoxy-2-methyl-1H- 552 551 304indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]isoquinolinium bis(trifluoroacetate) 5265-{4-[(Dimethylammonio)methyl]phenyl}- 558 557 3042-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H- imidazol-1-iumbis(trifluoroacetate) 527 4-Methoxy-2-[2-((1S)-1-{[(1- 478 477 307methylazetidinium-3-yl)carbonyl]amino}- 7-oxononyl)-1H-imidazol-1-ium-5-yl]quinolinium tris(trifluoroacetate) 5285-(2-Carboxyphenyl)-2-((1S)-1-{[(5- 545 544 304methoxy-2-methyl-1H-indol-3- yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium trifluoroacetate 5295-[4-(Dimethylammonio)phenyl]-2-((1S)- 544 543 3041-{[(5-methoxy-2-methyl-1H-indol-3- yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium bis(trifluoroacetate) 5302-((1S)-7-Oxo-1-{[(4,5,6,7-tetrafluoro-1H- 529 528 1indol-3-yl)acetyl]amino}nonyl)-5-phenyl- 1H-imidazol-1-iumtrifluoroacetate 531 2-((1S)-1-{[(5-Fluoro-2-methyl-1H-indol- 489 488 13-yl)acetyl]amino}-7-oxononyl)-5-phenyl- 1H-imidazol-1-iumtrifluoroacetate 532 1-Methyl-N-{(1S)-1-[5-(2-naphthyl)-1,3,4- 449 448308 oxadiazol-2-yl]-7-oxononyl}azetidine-3- carboxamide 5332-{(1S)-7-Oxo-1-[(1H-pyrrolo[2,3- 458 457 1b]pyridin-3-ylacetyl)amino]nonyl}-5- phenyl-1H-imidazol-1-iumtrifluoroacetate 534 4-({[(1S)-6-Carboxy-1-(5-phenyl-1H- 425 424 107imidazol-1-ium-2- yl)hexyl]amino}carbonyl)-1- azoniabicyclo[2.2.2]octanebis(trifluoroacetate) 535 4-({[(1S)-7-(Methoxyamino)-7-oxo-1-(5- 454 453108 phenyl-1H-imidazol-1-ium-2- yl)heptyl]amino}carbonyl)-1-azoniabicyclo[2.2.2]octane bis(trifluoroacetate) 5361-Methyl-4-({[(1S)-7-oxo-1-(4-phenyl-1H- 479 478 320imidazol-3-ium-2-yl)-7-(2- thienyl)heptyl]amino}carbonyl)piperidiniumbis(trifluoroacetate) 537 2-{(1S)-7-Oxo-1-[(1H-pyrrolo[3,2- 458 457 1c]pyridin-3-ylacetyl)amino]nonyl}-5- phenyl-1H-imidazol-1-iumtrifluoroacetate 538 2-((1S)-1-{[(5-Methoxy-1H-pyrrolo[2,3- 488 487 1c]pyridin-3-yl)acetyl]amino}-7-oxononyl)- 5-phenyl-1H-imidazol-1-iumtrifluoroacetate 539 5-(2-Fluoroquinolin-3-yl)-2-((1S)-1-{[(1- 466 465305 methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-3-ium bis(trifluoroacetate) 5402-((1S)-1-{[(1-Methylazetidinium-3- 449 448 305yl)carbonyl]amino}-7-oxononyl)-5- quinoxalin-6-yl-1H-imidazol-3-iumbis(trifluoroacetate) 541 8-Methoxy-5-[2-((1S)-1-{[(1- 478 477 305methylazetidinium-3-yl)carbonyl]amino}- 7-oxononyl)-1H-imidazol-3-ium-5-yl]quinolinium tris(trifluoroacetate) 5425-[4-(Dimethylamino)phenyl]-2-((1S)-1- 440 439 305{[(1-methylazetidinium-3- yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-3-ium bis(trifluoroacetate) 5432-Methyl-1-({[(1S)-7-oxo-1-(5-phenyl-1H- 473 472 1 imidazol-1-ium-2-yl)nonyl]amino}carbonyl)-1,2,3,4- tetrahydroisoquinoliniumbis(trifluoroacetate) 544 5-(3-Carboxyphenyl)-2-{(1S)-7-oxo-1-[(2- 453454 307 thienylcarbonyl)amino]nonyl}-1H- imidazol-3-ium trifluoroacetate545 4-Methoxy-2-(2-{(1S)-1-[(3-morpholin-4- 521 522 307ium-4-ylpropanoyl)amino]-7-oxononyl}- 1H-imidazol-1-ium-5-yl)quinoliniumtrichloride 546 2-[2-((1S)-1-{[3-(1H-Imidazol-1-ium-1- 502 503 307yl)propanoyl]amino}-7-oxononyl)-1H- imidazol-1-ium-5-yl]-4-methoxyquinolinium trichloride 5472-[2-((1S)-1-{[(4-Acetylpiperazin-1-ium- 548 549 3071-yl)acetyl]amino}-7-oxononyl)-1H- imidazol-1-ium-5-yl]-4-methoxyquinolinium trichloride 548 2-[2-((1S)-1- 465 466 307{[(Dimethylammonio)acetyl]amino}-7- oxononyl)-1H-imidazol-1-ium-5-yl]-4-methoxyquinolinium trichloride 549 4-Methoxy-2-(2-{(1S)-7-oxo-1- 505 506307 [(piperidinium-1-ylacetyl)amino]nonyl}-1H-imidazol-1-ium-5-yl)quinolinium trichloride 5504-Methoxy-2-[2-((1S)-1-{[(4- 520 521 307 methylpiperazin-4-ium-1-yl)acetyl]amino}-7-oxononyl)-1H- imidazol-1-ium-5-yl]quinoliniumtrichloride 551 4-Methoxy-2-[2-((1S)-1-{[(4- 507 508 307methylmorpholin-4-ium-2- yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]quinolinium tris(trifluoroacetate) 5524-Methoxy-2-[2-((1S)-1-{[3-(4- 534 535 307 methylpiperazin-4-ium-1-yl)propanoyl]amino}-7-oxononyl)-1H- imidazol-1-ium-5-yl]quinoliniumtris(trifluoroacetate) 553 4-Methoxy-2-[2-((1S)-1-{[(4- 534 535 307methylpiperazin-4-ium-1- yl)(oxo)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]quinolinium tris(trifluoroacetate) 5542-[(1S)-1-({[1-(N,N- 548 549 307 Dimethylglycyl)azetidin-3-yl]carbonyl}amino)-7-oxononyl]-5-(4-methoxyquinolin-2-yl)-1H-imidazol-1-ium trifluoroacetate 5552-[(1S)-1-({[1-(2- 521 522 307 Methoxyethyl)azetidinium-3-yl]carbonyl}amino)-7-oxononyl]-5-(4-methoxyquinolin-2-yl)-1H-imidazol-1-ium bis(trifluoroacetate) 5561-Methyl-3-[({(1S)-1-[5-(1,8- 450 451 309naphthyridin-2-yl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}amino)carbonyl]azetidinium formate 5571-Methyl-3-[({(1S)-1-[5-(1,6- 450 451 309naphthyridin-2-yl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}amino)carbonyl]azetidinium formate 5581-Methyl-3-[({(1S)-1-[5-(1,6- 450 451 309naphthyridin-8-yl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}amino)carbonyl]azetidinium formate 5593-({(1S)-1-[5-(4-Methoxyquinolin-2-yl)- 481 482 3091,3,4-oxadiazol-2-yl]-7-oxononyl}amino)-N,N-dimethyl-3-oxopropan-1-aminium formate 5604-[({(1S)-1-[5-(4-Methoxyquinolin-2-yl)- 519 520 3091,3,4-oxadiazol-2-yl]-7- oxononyl}amino)carbonyl]-1-azoniabicyclo[2.2.2]octane formate 5612-((1S)-1-{[(1-methylazetidinium-3- 463 464 305yl)carbonyl]amino}-7-oxononyl)-5-(2- oxo-1,2-dihydroquinolin-3-yl)-1H-imidazol-3-ium bis(trifluoroacetate) 562N-{(1S)-1-[5-(4-Methoxyquinolin-2-yl)- 540 541 3071,3,4-oxadiazol-2-yl]-7-oxononyl}-2-(1H-pyrrolo[3,2-c]pyridin-3-yl)acetamide 5635-(4-Methoxyquinolin-2-yl)-2-{(1S)-7- 538 539 307oxo-1-[(1H-pyrrolo[3,2-c]pyridin-3-ylacetyl)amino]nonyl}-1H-imidazol-1-ium trifluoroacetate 5645-(3-Carboxyphenyl)-2-((1S)-1-{[(1- 468 470 307methylpiperidin-4-yl)carbonyl]amino}-7- oxononyl)-1H-imidazol-3-iumtrifluoroacetate 565 5-(3-Carboxyphenyl)-2-{(1S)-1- 470 471 307[(morpholin-4-ylacetyl)amino]-7- oxononyl}-1H-imidazol-3-iumtrifluoroacetate 566 5-(3-Carboxyphenyl)-2-{(1S)-1-[(N,N- 428 429 307dimethylglycyl)amino]-7-oxononyl}-1H- imidazol-3-ium trifluoroacetate567 2-((1S)-1-{[(1-Methylpiperidin-4- 545 546 307yl)carbonyl]amino}-7-oxononyl)-5-(3- {[(methylsulfonyl)amino

]carbonyl}phenyl)- 1H-imidazol-3-ium trifluoroacetate 5682-((1S)-1-{[3-(3-Methoxyazetidinium-1- 492 493 305yl)propanoyl]amino}-7-oxononyl)-5- quinoxalin-6-yl-1H-imidazol-1-iumbis(trifluoroacetate) 569 3-({[(1S)-7-Oxo-1-(5-quinoxalin-6-yl-1H- 488489 305 imidazol-3-ium-2- yl)nonyl]amino}carbonyl)-1-azoniabicyclo[2.2.2]octane bis(trifluoroacetate) 5704-({[(1S)-7-Oxo-1-(5-quinoxalin-6-yl-1H- 488 489 305 imidazol-1-ium-2-yl)nonyl]amino}carbonyl)-1- azoniabicyclo[2.2.2]octanebis(trifluoroacetate) 571 5-(2-Methoxyquinolin-3-yl)-2-((1S)-1- 477 478305 {[(1-methylazetidinium-3- yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-3-ium dichloride 572 2-((1S)-1- 465 466 307{[(Dimethylammonio)acetyl]amino}-7-oxononyl)-5-(4-methoxyquinolin-2-yl)- 1H-imidazol-1-ium dichloride 5733-[({(1S)-1-[5-(2-Methoxyquinolin-3-yl)- 477 478 3051H-imidazol-2-yl]-7- oxononyl}amino)carbonyl]-1- methylazetidiniumchloride 574 N-{(1S)-1-[5-(2-methoxyquinolin-3-yl)- 477 478 3291H-imidazol-2-yl]-7-oxononyl}-1- methylazetidine-3-carboxamide 575N-{(1S)-7-[Methoxy(methyl)amino]-1-[5- 508 509 316(2-methoxyquinolin-3-yl)-1H-imidazol-2-yl]-7-oxoheptyl}-1-methylazetidine-3- carboxamide

What is claimed is:
 1. A compound of formula (I):

wherein: p is 0, 1, 2, 3, 4 or 5; q is 2, 3 or 4; t is 0 or 1; D isabsent, (CH₂)_(b) or (CH═CH)_(c); b is 1, 2 or 3; c is 1, 2 or 3; Arepresents CH or N; Y represents NR^(e), O or S; Z represents N orCR^(f); X is C or S═O; R¹ is hydrogen, hydroxy, halogen,C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆alkyl, haloC₁₋₆alkyl,N(R^(h))₂ wherein R^(h) is independently selected from hydrogen,C₁₋₆alkyl, C₆₋₁₀aryl and C₆₋₁₀arylC₁₋₆alkyl; C₃₋₁₀cycloalkyl, C₆₋₁₀aryl,5 or 6 membered saturated or partially saturated heterocycle containing1, 2 or 3 heteroatoms independently selected from N, O and S, 5 memberedunsaturated heterocycle containing 1, 2, 3 or 4 heteroatomsindependently selected from O, N and S, but not more than one of whichis O or S, 6 membered unsaturated heterocycle containing 1, 2 or 3nitrogen atoms, or 8-13 membered unsaturated or partially saturatedheterocycle containing heteroatoms independently selected from O, N andS; any of which rings being optionally substituted by one or more groupsindependently chosen from cyano, halogen, nitro, oxo, hydroxy,C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₁₋₆alkylcarbonyl,C₁₋₆alkoxycarbonyl, carboxy, C₆₋₁₀aryl, C₆₋₁₀aryloxy, C₆₋₁₀arylcarbonyl,N(R^(a))₂ wherein R^(a) is independently selected from hydrogen,C₁₋₆alkyl, C₆₋₁₀aryl, C₁₋₆alkylcarbonyl and C₆₋₁₀arylcarbonyl;C₁₋₆alkylN(R^(a))₂ and (CO)_(d)R^(k) wherein d is 0 or 1 and R^(k) is asdefined below; R² is C₁₋₆alkyl, R³ is hydrogen, halogen, hydroxy, cyano,C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy,C₃₋₁₀cycloalkyl, haloC₃₋₁₀cycloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, nitro,amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, C₆₋₁₀aryl,C₆₋₁₀arylC₁₋₆alkyl, C₆₋₁₀arylC₁₋₆alkoxy; 6-13 membered partiallysaturated hydrocarbon ring; 4, 5 or 6 membered saturated or partiallysaturated heterocycle containing 1, 2 or 3 heteroatoms independentlyselected from N, O and S, optionally bridged by a C₁-C₄alkyl group; 5membered unsaturated heterocycle containing 1, 2, 3 or 4 heteroatomsindependently selected from N, O and S, but not more than one of whichis O or S; 6 membered unsaturated heterocycle containing 1, 2 or 3nitrogen atoms; or a 7-15 membered saturated, partially saturated orunsaturated heterocycle containing heteroatoms independently selectedfrom N, O or S; any of which rings being optionally substituted by oneor more groups independently chosen from (CH₂)_(m)(CO)_(n)R^(d); m is 0,1, 2 or 3; n is 0, 1 or 2; R⁴ and R⁵ are independently selected fromhydrogen and C₁₋₆alkyl; R⁶ and R⁸ are independently hydrogen, C₁₋₆alkyl,a 5 or 6 membered saturated or partially saturated heterocyclecontaining 1, 2 or 3 heteroatoms independently selected from N, O and Sor a 6 membered unsaturated heterocycle containing 1, 2 or 3 nitrogenatoms; each of which rings being optionally substituted by one or moregroups independently chosen from halogen, nitro, amino, cyano, oxo,hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy,C₃₋₁₀cycloalkyl, C₂₋₆alkenyl and C₂₋₆alkynyl; or R⁶ and R⁸ togetherrepresent an oxo group; R^(g) is C₁₋₆alkyl, haloC₁₋₆alkyl, amino,C₁₋₆alkylamino or di(C₁₋₆alkyl)amino; each R^(d) is halogen, hydroxy,cyano, C₁₋₆alkyl, haloC₁₋₆alkyl, haloC₁₋₆alkylcarbonyl,haloC₁₋₆alkylcarbonyloxy, C₁₋₆alkoxy, haloC₁₋₆alkoxy, carboxy,C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl, nitro, oxo, SO₂N(R^(e))₂,N(R^(e))₂ wherein R^(e) is independently selected from hydrogen,C₁₋₆alkyl, C₁₋₆alkylcarbonyl, carboxy and C₁₋₆alkyloxycarbonyl;C₁₋₆alkylN(R^(e))₂, C₆₋₁₀aryl; C₆₋₁₀arylC₁₋₆alkoxy, 5 or 6 memberedsaturated or partially saturated heterocycle containing 1, 2 or 3heteroatoms independently selected from N, O or S, optionally bridged bya C₁₋₄-alkyl group; 5 membered unsaturated heterocycle containing 1, 2,3 or 4 heteroatoms independently selected from N, O and S, but not morethan one of which is O or S; a 5 or 6 membered spiro ring containingzero, one or two heteroatoms independently selected from N, O or S, or a6 membered unsaturated heterocycle containing 1, 2 or 3 nitrogen atoms;any of which rings may be optionally substituted by one or more groupsindependently chosen from halogen, hydroxy, amino, cyano, C₁₋₆alkyl,haloC₁₋₆alkyl, C₁₋₆alkoxy and haloC₁₋₆alkoxy; R^(e) represents hydrogenor C₁₋₆alkyl; R^(f) represents hydrogen, C₁₋₆alkyl or C₆₋₁₀aryloptionally substituted by up to two groups selected from halogen, cyano,C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl or haloC₁₋₆alkoxy; R^(k) isNHSO₂R^(g), 5 or 6 membered saturated or partially saturated heterocyclecontaining 1, 2 or 3 heteroatoms independently selected from N, O and Sor a 5 membered unsaturated heterocycle containing 1, 2, 3 or 4heteroatoms independently selected from N, O and S, but not more thanone of which is O or S; any of which rings being optionally substitutedby one or more groups independently selected from halogen and C₁₋₆alkyl;or a pharmaceutically acceptable salt or tautomer thereof.
 2. Thecompound according to claim 1 wherein: R¹ is a 5 or 6 membered saturatedor partially saturated heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, 5 membered unsaturatedheterocycle containing 1, 2, 3 or 4 heteroatoms independently selectedfrom O, N and S, but not more than one of which is O or S, 6 memberedunsaturated heterocycle containing 1, 2 or 3 nitrogen atoms, or 8-13membered unsaturated or partially saturated heterocycle containingheteroatoms independently selected from O, N and S; any of which ringsbeing optionally substituted by one or more groups independently chosenfrom cyano, halogen, nitro, oxo, hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl,C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl,carboxy, C₆₋₁₀aryl, C₆₋₁₀aryloxy, C₆₋₁₀arylcarbonyl, N(R^(a))₂ whereinR^(a) is independently selected from hydrogen, C₁₋₆alkyl, C₆₋₁₀aryl,C₁₋₆alkylcarbonyl and C₆₋₁₀arylcarbonyl; C₁₋₆alkylN(R^(a))₂ and(CO)_(d)R^(k) wherein d is 0 or 1 and R^(k) is as defined in claim
 1. 3.The compound according to claim 1 wherein: R³ isazoniabicyclo[2.2.1]heptanyl, azoniabicyclo[2.2.2]octanyl, thiazolyl,pyrazolyl, isoxazolyl, thiadiazolyl, benzothienyl, benzothiadiazolyl,benzoxadiazolyl, dihydrobenzofuryl, dihydrothiazolopyrimidinyl,dihydrobenzodioxinyl, dihydrobenzoxazinyl, benzimidazolyl,triazolopyrimidinyl, dihydrobenzoxazolyl, dihydroindolyl,dihydroquinazolinyl, dihydrophthalazinyl, indazolyl, benzisoxazolyl,benzotriazolyl, tetrahydrobetacarbolinyl, dihydroisoindolyl,tetrahydronaphthyridinyl, tetrazolyl, thiomorpholinyl, azetidinyl,dihydroisochromenyl, dihydrochromenyl, tetrahydroquinolinyl, indenyl,dihydrobenzothiazolyl, imidazothiazolyl, naphthyridinyl,tetrahydroindazolyl, tetrahydrobenzothienyl, hexahydronaphthyridinyl,tetrahydropyridonaphthyridinyl, tetrahydroisoquinolinyl,tetrahydroimidazopyridinyl, tetrahydroimidazopyrazinyl orpyrrolopyridinyl; any of which rings being optionally substituted by oneor more groups independently chosen from (CH₂)_(m)(CO)_(n)R^(d),whereinm, n and R^(d) are as defined in claim
 1. 4. The compound of claim 1 offormula II:

wherein: R¹, R³, R⁵, R⁶, R⁸, X, p and t are as defined in any one ofclaim 1, 3 or 4; D is absent, CH₂, CH₂CH₂ or CH═CH; A represents CH orN; Y represents NR^(e), O or S; Z represents N or CR^(f); R⁷ representsC₁₋₆alkyl R^(e) represents hydrogen or C₁₋₆alkyl; R^(f) representshydrogen, C₁₋₆alkyl or C₆₋₁₀aryl optionally substituted by up to twogroups selected from halogen, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkyl or haloC₁₋₆alkoxy; R^(g) is C₁₋₆alkyl, haloC₁₋₆alkyl,amino, C₁₋₆alkylamino or di(C₁₋₆alkyl)amino; m is 0, 1, 2 or 3; or apharmaceutically acceptable salt or tautomer thereof.
 5. The compoundaccording to claim 1 of formula IB:

wherein D, R² and X are as defined in claim 1; R¹ is a 8-13 memberedunsaturated or partially saturated heterocycle containing heteroatomsindependently selected from O, N and S; any of which rings beingoptionally substituted by one or more groups independently chosen fromcyano, halogen, nitro, oxo, hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl,C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl,carboxy, C₆₋₁₀aryl, C₆₋₁₀aryloxy, C₆₋₁₀arylcarbonyl, N(R^(a))₂ whereinR^(a) is independently selected from hydrogen, C₁₋₆alkyl, C₆₋₁₀aryl,C₁₋₆alkylcarbonyl and C₆₋₁₀arylcarbonyl; C₁₋₆alkylN(R^(a))₂ and(CO)_(d)R^(k) wherein d is 0 or 1; R^(k) is NHSO₂R^(g), 5 or 6 memberedsaturated or partially saturated heterocycle containing 1, 2 or 3heteroatoms independently selected from N, O and S or a 5 memberedunsaturated heterocycle containing 1, 2, 3 or 4 heteroatomsindependently selected from N, O and S, but not more than one of whichis O or S; any of which rings being optionally substituted by one ormore groups independently selected from halogen and C₁₋₆alkyl; R^(g) isC₁₋₆alkyl, haloC₁₋₆alkyl, amino, C₁₋₆alkylamino or di(C₁₋₆alkyl)amino;R³ is azoniabicyclo[2.2.1]heptanyl, azoniabicyclo[2.2.2]octanyl,thiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, benzothienyl,benzothiadiazolyl, benzoxadiazolyl, dihydrobenzofuryl,dihydrothiazolopyrimidinyl, dihydrobenzodioxinyl, dihydrobenzoxazinyl,benzimidazolyl, triazolopyrimidinyl, dihydrobenzoxazolyl,dihydroindolyl, dihydroquinazolinyl, dihydrophthalazinyl, indazolyl,benzisoxazolyl, benzotriazolyl, tetrahydrobetacarbolinyl,dihydroisoindolyl, tetrahydronaphthyridinyl, tetrazolyl,thiomorpholinyl, azetidinyl, dihydroisochromenyl, dihydrochromenyl,tetrahydroquinolinyl, dihydrobenzothiazolyl, imidazothiazolyl,naphthyridinyl, tetrahydroindazolyl, tetrahydrobenzothienyl,hexahydronaphthyridinyl, tetrahydropyridonaphthyridinyl,tetrahydroisoquinolinyl, tetrahydroimidazopyridinyl,tetrahydroimidazopyrazinyl or pyrrolopyridinyl; any of which rings beingoptionally substituted by one or more groups independently chosen from(CH₂)_(m)(CO)_(n)R^(d); m is 0, 1, 2 or 3; n is 0, 1 or 2; R^(d) ishalogen, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, carboxy,C₁₋₆alkoxycarbonyl, nitro, aminosulfonyl, (C₁₋₆alkylcarbonyl)amino,morpholinyl, piperazinyl, thiazolyl, pyrazolyl, isoxazolyl, pyridinyl,oxo, haloC₁₋₆alkyl, phenyl or pyrrolidinyl, hydroxy, piperidinespiro,C₆₋₁₀arylC₁₋₆alkoxy, di(C₁₋₆alkyl)amino, C₁₋₆alkylcarbonyl ordi(C₁₋₆alkylamino)C₁₋₆alkyl; any of which rings being optionallysubstituted by one or more groups independently chosen from C₁₋₆alkyland haloC₁₋₆alkyl; or a pharmaceutically acceptable salt or tautomerthereof.
 6. A compound selected from:2-{(1S)-1-[(carboxycarbonyl)amino]-7-oxononyl}-5-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate;2-((1S)-1-{[morpholin-4-yl(oxo)acetyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate;5-(2-naphthyl)-2-{(1S)-7-oxo-1-[(trifluoroacetyl)amino]nonyl}-1H-imidazol-1-iumtrifluoroacetate;2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-iumdichloride;2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-[4-(1H-pyrazol-1-yl)phenyl]-1H-imidazol-3-iumtrifluoroacetate;5-(2-methoxyquinolin-3-yl)-2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-3-iumbis(trifluoroacetate);2-((1S)-1-{[3-(dimethylammonio)propanoyl]amino}-7-oxononyl)-5-(2-naphthyl)-1H-imidazol-3-iumdichloride;4-methoxy-2-[2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]quinoliniumtrichloride;N-{(1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]-5-oxoheptyl}quinuclidine-4-carboxamide;N-{(1S)-1-[5-(4-methoxyquinolin-2-yl)-1,3,4-oxadiazol-2-yl]-7-oxononyl}-1-methylazetidine-3-carboxamide;5-(hydroxymethyl)-2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-iumtrifluoroacetate;4-{[2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-ium-5-yl]methyl}morpholin-4-iumbis(trifluoroacetate);2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-1H-imidazol-1-iumtrifluoroacetate;5-(2-carboxyethyl)-2-(1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-iumtrifluoroacetate;5-acetyl-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-iumtrifluoroacetate;5-cyclohexyl-2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxononyl)-1H-imidazol-1-iumtrifluoroacetate;2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoundecyl)-5-phenyl-1H-imidazol-1-iumtrifluoroacetate;2-((1S)-7-cyclopropyl-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-phenyl-1H-imidazol-1-iumtrifluoroacetate;2-((1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-9-methyl-7-oxodecyl)-5-phenyl-1H-imidazol-1-iumtrifluoroacetate;2-((1S)-8-hydroxy-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-phenyl-1H-imidazol-1-iumtrifluoroacetate;2-((1S)-7-(2-furyl)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate;2-[(1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-8-(methylsulfinyl)-7-oxooctyl]-5-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate;2-[(1S)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-8-(methylsulfonyl)-7-oxooctyl]-5-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate;2-((1S)-8-(aminosulfonyl)-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxooctyl)-5-(2-naphthyl)-1H-imidazol-1-iumtrifluoroacetate;1-methyl-4-({[(1S)-7-oxo-1-(4-phenyl-1H-imidazol-3-ium-2-yl)-7-pyridin-2-ylheptyl]amino}carbonyl)piperidiniumbis(trifluoroacetate);2-((1S)-7-amino-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-oxoheptyl)-5-(2-naphthyl)-1H-imidazol-3-iumtrifluoroacetate;2-((1S)-6-carboxy-1-{[(dimethylamino)sulfonyl]amino}hexyl)-5-(2-naphthyl)-1H-imidazol-3-iumtrifluoroacetate;2-((1S)-7-(methylamino)-7-oxo-1-{[(1-pyridin-2-ylpiperidin-3-yl)carbonyl]amino}heptyl)-5-(2-naphthyl)-1H-imidazol-3-iumtrifluoroacetate;2-[(1S)-1-{[(benzylamino)carbonyl]amino}-7-(methylamino)-7-oxoheptyl]-5-(2-naphthyl)-1H-imidazol-3-iumtrifluoroacetate; and5-(2-methoxyquinolin-3-yl)-2-415)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-3-ium-L-tartrate;and the pharmaceutically acceptable free bases, salts, alternative saltsand stereoisomers thereof.
 7. A tartrate salt of a compound of claim 1.8. A pharmaceutical composition comprising a compound of claim 1 or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 9. The compound of claim 1 that is5-(2-Methoxyquinolin-3-yl)-2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-3-ium-L-tartrateor a stereoisomer thereof.
 10. The compound of claim 1 that is5-(2-Methoxyquinolin-3-yl)-2-((1S)-1-{[(1-methylazetidinium-3-yl)carbonyl]amino}-7-oxononyl)-1H-imidazol-3-ium-L-tartrate.11. The compound of claim 1 that is(N-{(1S)-1-[5-(2-methoxyquinolin-3-yl)-1H-imidazol-2-yl]-7-oxononyl}-1-methylazetidine-3-carboxamide)or a pharmaceutically acceptable salt thereof or stereoisomer thereof.12. The compound of claim 1 that is(N-{(1S)-1-[5-(2-methoxyquinolin-3-yl)-1H-imidazol-2-yl]-7-oxononyl}-1-methylazetidine-3-carboxamide)or a pharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition comprising a compound of claim 9 and a pharmaceuticallyacceptable carrier.
 14. A pharmaceutical composition comprising acompound of claim 10 and a pharmaceutically acceptable carrier.
 15. Apharmaceutical composition comprising a compound of claim 11 and apharmaceutically acceptable carrier.
 16. A pharmaceutical compositioncomprising a compound of claim 12 and a pharmaceutically acceptablecarrier.
 17. The compound of claim 1, Wherein D, R² and X are as definedin claim 1; R¹ is quinolinyl, isoquinolinyl, quinoxalinyl,tetrahydroisoquinolinyl, naphthyridinyl or dihydroquinolinyl, optionallysubstituted by one or more groups independently chosen from cyano,halogen, nitro, oxo, hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl, carboxy,C₆₋₁₀aryl, C₆₋₁₀aryloxy, C₆₋₁₀arylcarbonyl, N(R^(a))₂ wherein R^(a) isindependently selected from hydrogen, C₁₋₆alkyl, C₆₋₁₀aryl,C₁₋₆alkylcarbonyl and C₆₋₁₀arylcarbonyl; C₁₋₆alkylN(R^(a))₂ and(CO)_(d)R^(k) wherein d is 0 or 1; R^(k) is NHSO₂R^(g), 5 or 6 memberedsaturated or partially saturated heterocycle containing 1, 2 or 3heteroatoms independently selected from N, O and S or a 5 memberedunsaturated heterocycle containing 1, 2, 3 or 4 heteroatomsindependently selected from N, O and S, but not more than one of whichis O or S; any of which rings being optionally substituted by one ormore groups independently selected from halogen and C₁₋₆alkyl; R^(g) isC₁₋₆alkyl, haloC₁₋₆alkyl, amino, C₁₋₆alkylamino or di(C₁₋₆alkyl)amino;R³ is an azetidinyl optionally substituted by one or more groupsindependently chosen from (CH₂)_(m)(CO)_(n)R^(d); m is 0, 1, 2 or 3; nis 0, 1 or 2; R^(d) is halogen, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, carboxy, C₁₋₆alkoxycarbonyl, nitro, aminosulfonyl,(C₁₋₆alkylcarbonyl)amino, morpholinyl, piperazinyl, thiazolyl,pyrazolyl, isoxazolyl, pyridinyl, oxo, haloC₁₋₆alkyl, phenyl orpyrrolidinyl, hydroxy, piperidinespiro, C₆₋₁₀arylC₁₋₆alkoxy,di(C₁₋₆alkyl)amino, C₁₋₆alkylcarbonyl or di(C₁₋₆alkylamino)C₁₋₆alkyl;any of which rings being optionally substituted by one or more groupsindependently chosen from C₁₋₆alkyl and haloC₁₋₆alkyl.
 18. The compoundof claim 17, Wherein R¹ is as defined in claim 17; R² is C₁₋₆alkyl; R³is 1-methylazetidin-3-yl; D is a direct bond; X is C.